Clinical Practice Guidelines by the Infectious Diseases

Clinical Infectious Diseases Advance Access published January 4, 2011

IDSA GUIDELINES

Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus Aureus Infections in Adults and Children

Catherine Liu,1 Arnold Bayer,3,5 Sara E. Cosgrove,6 Robert S. Daum,7 Scott K. Fridkin,8 Rachel J. Gorwitz,9 Sheldon L. Kaplan,10 Adolf W. Karchmer,11 Donald P. Levine,12 Barbara E. Murray,14 Michael J. Rybak,12,13 David A. Talan,4,5 and Henry F. Chambers1,2 1Department of Medicine, Division of Infectious Diseases, University of California-San Francisco, San Francisco, California; 2Division of Infectious Diseases, Downloaded from San Francisco General Hospital, San Francisco, CA, 3Division of Infectious Diseases, Harbor-UCLA Medical Center, Torrance, CA, 4Divisions of Emergency Medicine and Infectious Diseases, Olive View-UCLA Medical Center, Sylmar, CA; 5Department of Medicine, David Geffen School of Medicine at University of California Los Angeles; 6Division of Infectious Diseases, Johns Hopkins Medical Institutions, Baltimore, Maryland; 7Department of Pediatrics, Section of Infectious Diseases, University of Chicago, Chicago, Illinois; 8,9Division of Healthcare Quality Promotion, Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; 10Department of Pediatrics, Section of Infectious Diseases, Baylor College of 11 Medicine, Houston, Texas; Division of Infectious Diseases, Beth Israel Deaconess Medicine Center, Harvard Medical School, Boston, Massachusetts; cid.oxfordjournals.org 12 Department of Medicine, Division of Infectious Diseases, Wayne State University, Detroit Receiving Hospital and University Health Center, Detroit, Michigan; 13Deparment of Pharmacy Practice, Wayne State University, Detroit Michigan; and 14Division of Infectious Diseases and Center for the Study of Emerging and Re-emerging Pathogens, University of Texas Medical School, Houston, Texas

Evidence-based guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA). The at GATA Library on January 11, 2011 guidelines are intended for use by health care providers who care for adult and pediatric patients with MRSA infections. The guidelines discuss the management of a variety of clinical syndromes associated with MRSA disease, including skin and soft tissue infections (SSTI), bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system (CNS) infections. Recommendations are provided regarding vancomycin dosing and monitoring, management of infections due to MRSA strains with reduced susceptibility to vancomycin, and vancomycin treatment failures.

EXECUTIVE SUMMARY constitutes the ﬁrst guidelines of the IDSA on the treatment of MRSA infections. The primary objective of these MRSA is a signiﬁcant cause of both health care–associated guidelines is to provide recommendations on the man- and community-associated infections. This document agement of some of the most common clinical syndromes encountered by adult and pediatric clinicians who care for Received 28 October 2010; accepted 17 November 2010. patients with MRSA infections. The guidelines address It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment issues related to the use of vancomycin therapy in the with respect to particular patients or special clinical situations. The IDSA considers treatment of MRSA infections, including dosing and adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each monitoring, current limitations of susceptibility testing, patient's individual circumstances. and the use of alternate therapies for those patients with Correspondence: Catherine Liu, MD, Dept of Medicine, Div of Infectious Diseases, University of California–San Francisco, San Francisco, California, 94102 vancomycin treatment failure and infection due to strains ([email protected]). with reduced susceptibility to vancomycin. The guidelines Clinical Infectious Diseases 2011;1–38 do not discuss active surveillance testing or other Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, MRSA infection–prevention strategies in health care set- please e-mail:[email protected]. 1058-4838/2011/523-0001$37.00 tings, which are addressed in previously published DOI: 10.1093/cid/ciq146 guidelines [1, 2]. Each section of the guidelines begins

Clinical Practice Guidelines d CID 2011:52 (1 February) d 1 with a specific clinical question and is followed by numbered a tetracycline (doxycycline or minocycline) (A-II), and linezolid recommendations and a summary of the most-relevant evidence (A-II). If coverage for both b-hemolytic streptococci and in support of the recommendations. Areas of controversy in CA-MRSA is desired, options include the following: whichdataarelimitedorconflictingandwhereadditionalre- clindamycin alone (A-II) or TMP-SMX or a tetracycline in search is needed are indicated throughout the document and are combination with a b-lactam (eg, amoxicillin) (A-II) or linezolid highlighted in the Research Gaps section. The key recom- alone (A-II). mendations are summarized below in the Executive Summary; 6. The use of rifampin as a single agent or as adjunctive each topic is discussed in greater detail within the main body of therapy for the treatment of SSTI is not recommended (A-III). the guidelines. 7. For hospitalized patients with complicated SSTI (cSSTI; Please note that specific recommendations on vancomycin defined as patients with deeper soft-tissue infections, surgical/ dosing and monitoring are not discussed in the sections for each traumatic wound infection, major abscesses, cellulitis, and clinical syndrome but are collectively addressed in detail in infected ulcers and burns), in addition to surgical debridement Section VIII. and broad-spectrum antibiotics, empirical therapy for MRSA should be considered pending culture data. Options I. What is the management of skin and soft-tissue infections include the following: intravenous (IV) vancomycin (A-I), oral (SSTIs) in the era of community-associated MRSA (CA-MRSA)? (PO) or IV linezolid 600 mg twice daily (A-I), daptomycin

SSTIs 4 mg/kg/dose IV once daily (A-I), telavancin 10 mg/kg/dose IV Downloaded from once daily (A-I), and clindamycin 600 mg IV or PO 3 times 1. For a cutaneous abscess, incision and drainage is the a day (A-III).Ab-lactam antibiotic (eg, cefazolin) may be primary treatment (A-II). For simple abscesses or boils, considered in hospitalized patients with nonpurulent cellulitis incision and drainage alone is likely to be adequate, but with modiﬁcation to MRSA-active therapy if there is no clinical additional data are needed to further deﬁne the role of

response (A-II). Seven to 14 days of therapy is recommended cid.oxfordjournals.org antibiotics, if any, in this setting. but should be individualized on the basis of the patient’s 2. Antibiotic therapy is recommended for abscesses clinical response. associated with the following conditions: severe or extensive 8. Cultures from abscesses and other purulent SSTIs are disease (eg, involving multiple sites of infection) or rapid recommended in patients treated with antibiotic therapy, progression in presence of associated cellulitis, signs and patients with severe local infection or signs of systemic illness, symptoms of systemic illness, associated comorbidities or patients who have not responded adequately to initial treatment, at GATA Library on January 11, 2011 immunosuppression, extremes of age, abscess in an area and if there is concern for a cluster or outbreak (A-III). difﬁcult to drain (eg, face, hand, and genitalia), associated septic phlebitis, and lack of response to incision and drainage Pediatric considerations alone (A-III). 9. For children with minor skin infections (such as impetigo) 3. For outpatients with purulent cellulitis (eg, cellulitis and secondarily infected skin lesions (such as eczema, ulcers, or associated with purulent drainage or exudate in the absence of lacerations), mupirocin 2% topical ointment can be used (A-III). a drainable abscess), empirical therapy for CA-MRSA is 10. Tetracyclines should not be used in children ,8 years of recommended pending culture results. Empirical therapy for age (A-II). infection due to b-hemolytic streptococci is likely to be 11. In hospitalized children with cSSTI, vancomycin is unnecessary (A-II). Five to 10 days of therapy is recom- recommended (A-II). If the patient is stable without ongoing mended but should be individualized on the basis of the bacteremia or intravascular infection, empirical therapy with patient’s clinical response. clindamycin 10–13 mg/kg/dose IV every 6–8 h (to administer 4. For outpatients with nonpurulent cellulitis (eg, cellulitis 40 mg/kg/day) is an option if the clindamycin resistance rate is with no purulent drainage or exudate and no associated low (eg, ,10%) with transition to oral therapy if the strain is abscess), empirical therapy for infection due to b-hemolytic susceptible (A-II). Linezolid 600 mg PO/IV twice daily for streptococci is recommended (A-II). The role of CA-MRSA is children >12 years of age and 10 mg/kg/dose PO/IV every 8 h unknown. Empirical coverage for CA-MRSA is recommended for children ,12 years of age is an alternative (A-II). in patients who do not respond to b-lactam therapy and may be considered in those with systemic toxicity. Five to 10 days of II. What is the management of recurrent MRSA SSTIs? therapy is recommended but should be individualized on the Recurrent SSTIs basis of the patient’s clinical response. 5. For empirical coverage of CA-MRSA in outpatients with 12. Preventive educational messages on personal hygiene SSTI, oral antibiotic options include the following: clindamycin and appropriate wound care are recommended for all patients (A-II), trimethoprim-sulfamethoxazole (TMP-SMX) (A-II), with SSTI. Instructions should be provided to:

2 d CID 2011:52 (1 February) d Liu et al. i. Keep draining wounds covered with clean, dry bandages ii. Contacts should be evaluated for evidence of S. aureus (A-III). infection: ii. Maintain good personal hygiene with regular bathing and a. Symptomatic contacts should be evaluated and treated (A- cleaning of hands with soap and water or an alcohol-based III); nasal and topical body decolonization strategies may be hand gel, particularly after touching infected skin or an item considered following treatment of active infection (C-III). that has directly contacted a draining wound (A-III). b. Nasal and topical body decolonization of asymptomatic iii. Avoid reusing or sharing personal items (eg, disposable household contacts may be considered (C-III). razors, linens, and towels) that have contacted infected skin 18. The role of cultures in the management of patients with (A-III). recurrent SSTI is limited: 13. Environmental hygiene measures should be considered i. Screening cultures prior to decolonization are not in patients with recurrent SSTI in the household or community routinely recommended if at least 1 of the prior infections setting: was documented as due to MRSA (B-III). i. Focus cleaning efforts on high-touch surfaces (ie, surfaces ii. Surveillance cultures following a decolonization regimen that come into frequent contact with people’s bare skin each are not routinely recommended in the absence of an active day, such as counters, door knobs, bath tubs, and toilet seats) infection (B-III). that may contact bare skin or uncovered infections (C-III). III. What is the management of MRSA bacteremia and infective Downloaded from ii. Commercially available cleaners or detergents appropriate endocarditis? for the surface being cleaned should be used according to label Bacteremia and Infective Endocarditis, Native Valve instructions for routine cleaning of surfaces (C-III). 19. For adults with uncomplicated bacteremia (deﬁned as patients with positive blood culture results and the following:

14. Decolonization may be considered in selected cases if: cid.oxfordjournals.org exclusion of endocarditis; no implanted prostheses; follow-up i. A patient develops a recurrent SSTI despite optimizing blood cultures performed on specimens obtained 2–4 days wound care and hygiene measures (C-III). ii. Ongoing transmission is occurring among household after the initial set that do not grow MRSA; defervescence members or other close contacts despite optimizing wound within 72 h of initiating effective therapy; and no evidence of care and hygiene measures (C-III). metastatic sites of infection), vancomycin (A-II) or daptomycin 6mg/kg/doseIVoncedaily(AI) for at least 2 weeks. For at GATA Library on January 11, 2011 15. Decolonization strategies should be offered in conjunction complicated bacteremia (deﬁned as patients with positive blood with ongoing reinforcement of hygiene measures and may culture results who do not meet criteria for uncomplicated include the following: bacteremia), 4–6 weeks of therapy is recommended, depending i. Nasal decolonization with mupirocin twice daily for 5–10 on the extent of infection. Some experts recommend higher days (C-III). dosages of daptomycin at 8–10 mg/kg/dose IV once daily (B-III). ii. Nasal decolonization with mupirocin twice daily for 5–10 20. For adults with infective endocarditis, IV vancomycin days and topical body decolonization regimens with a skin (A-II) or daptomycin 6 mg/kg/dose IV once daily (A-I) for 6 antiseptic solution (eg, chlorhexidine) for 5–14 days or dilute weeks is recommended. Some experts recommend higher bleach baths. (For dilute bleach baths, 1 teaspoon per gallon dosages of daptomycin at 8–10 mg/kg/dose IV once daily of water [or ¼ cup per ¼ tub or 13 gallons of water] given (B-III). for 15 min twice weekly for 3 months can be considered.) 21. Addition of gentamicin to vancomycin is not recom- (C-III). mended for bacteremia or native valve infective endocarditis (A-II). 16. Oral antimicrobial therapy is recommended for the 22. Addition of rifampin to vancomycin is not recommen- treatment of active infection only and is not routinely re- ded for bacteremia or native valve infective endocarditis (A-I). commended for decolonization (A-III). An oral agent in 23. A clinical assessment to identify the source and extent of combination with rifampin, if the strain is susceptible, may be the infection with elimination and/or debridement of other considered for decolonization if infections recur despite above sites of infection should be conducted (A-II). measures (CIII). 24. Additional blood cultures 2–4 days after initial positive 17. In cases where household or interpersonal transmission cultures and as needed thereafter are recommended to is suspected: document clearance of bacteremia (A-II). i. Personal and environmental hygiene measures in the 25. Echocardiography is recommended for all adult patient and contacts are recommended (A-III). patients with bacteremia. Transesophageal echocardiography

Clinical Practice Guidelines d CID 2011:52 (1 February) d 3 (TEE) is preferred over transthoracic echocardiography (TTE) 34. In patients with MRSA pneumonia complicated by (A-II). empyema, antimicrobial therapy against MRSA should be used 26. Evaluation for valve replacement surgery is recommen- in conjunction with drainage procedures (A-III). ded if large vegetation (.10 mm in diameter), occurrence of Pediatric considerations >1 embolic event during the first 2 weeks of therapy, severe valvular insufficiency, valvular perforation or dehiscence, 35. In children, IV vancomycin is recommended (A-II). If decompensated heart failure, perivalvular or myocardial the patient is stable without ongoing bacteremia or intravas- abscess, new heart block, or persistent fevers or bacteremia cular infection, clindamycin 10–13 mg/kg/dose IV every 6–8 h are present (A-II). (to administer 40 mg/kg/day) can be used as empirical therapy if the clindamycin resistance rate is low (eg, ,10%) with Infective Endocarditis, Prosthetic Valve transition to oral therapy if the strain is susceptible (A-II). 27. IV vancomycin plus rifampin 300 mg PO/IV every 8 h Linezolid 600 mg PO/IV twice daily for children >12 years of for at least 6 weeks plus gentamicin 1 mg/kg/dose IV every 8 h age and 10 mg/kg/dose every 8 h for children ,12 years of age is for 2 weeks (B-III). an alternative (A-II). 28. Early evaluation for valve replacement surgery is V. What is the management of MRSA bone and joint infections? recommended (A-II). Osteomyelitis Downloaded from Pediatric considerations 36. Surgical debridement and drainage of associated soft- tissue abscesses is the mainstay of therapy and should be 29. In children, vancomycin 15 mg/kg/dose IV every 6 h is performed whenever feasible (A-II). recommended for the treatment of bacteremia and infective 37. The optimal route of administration of antibiotic endocarditis (A-II). Duration of therapy may range from 2 to 6 therapy has not been established. Parenteral, oral, or initial cid.oxfordjournals.org weeks depending on source, presence of endovascular infection, parenteral therapy followed by oral therapy may be used and metastatic foci of infection. Data regarding the safety and depending on individual patient circumstances (A-III). efficacy of alternative agents in children are limited, although 38. Antibiotics available for parenteral administration in- daptomycin 6–10 mg/kg/dose IV once daily may be an option clude IV vancomycin (B-II) and daptomycin 6 mg/kg/dose IV (C-III). Clindamycin or linezolid should not be used if there is once daily (B-II). Some antibiotic options with parenteral and oral routes of administration include the following: TMP-SMX concern for infective endocarditis or endovascular source of at GATA Library on January 11, 2011 infection but may be considered in children whose bacteremia 4 mg/kg/dose (TMP component) twice daily in combination rapidly clears and is not related to an endovascular focus (B-III). with rifampin 600 mg once daily (B-II), linezolid 600 mg twice 30. Data are insufficient to support the routine use of daily (B-II), and clindamycin 600 mg every 8 h (B-III). combination therapy with rifampin or gentamicin in children 39. Some experts recommend the addition of rifampin with bacteremia or infective endocarditis (C-III); the decision 600 mg daily or 300–450 mg PO twice daily to the antibiotic to use combination therapy should be individualized. chosen above (B-III). For patients with concurrent bacter- 31. Echocardiogram is recommended in children with con- emia, rifampin should be added after clearance of bacteremia. genital heart disease, bacteremia more than 2–3 days in duration, 40. The optimal duration of therapy for MRSA osteomye- or other clinical findings suggestive of endocarditis (A-III). litis is unknown. A minimum 8-week course is recommended (A-II). Some experts suggest an additional 1–3 months (and IV. What is the management of MRSA pneumonia? possibly longer for chronic infection or if debridement is not Pneumonia performed) of oral rifampin-based combination therapy with 32. For hospitalized patients with severe community- TMP-SMX, doxycycline-minocycline, clindamycin, or a fluo- acquired pneumonia defined by any one of the following: (1) roquinolone, chosen on the basis of susceptibilities (C-III). a requirement for intensive care unit (ICU) admission, (2) 41. Magnetic resonance imaging (MRI) with gadolinium is necrotizing or cavitary infiltrates, or (3) empyema, empirical the imaging modality of choice, particularly for detection of early osteomyelitis and associated soft-tissue disease (A-II). therapy for MRSA is recommended pending sputum and/or Erythrocyte sedimentation rate (ESR) and/or C-reactive pro- blood culture results (A-III). tein (CRP) level may be helpful to guide response to therapy 33. For health care–associated MRSA (HA-MRSA) or CA- (B-III). MRSA pneumonia, IV vancomycin (A-II) or linezolid 600 mg PO/IV twice daily (A-II) or clindamycin 600 mg PO/IV 3 times Septic Arthritis daily (B-III), if the strain is susceptible, is recommended for 7– 42. Drainage or debridement of the joint space should 21 days, depending on the extent of infection. always be performed (A-II).

4 d CID 2011:52 (1 February) d Liu et al. 43. For septic arthritis, refer to antibiotic choices for VI. What is the management of MRSA infections of the CNS? osteomyelitis (recommendation 37 above). A 3–4-week course Meningitis of therapy is suggested (A-III). 49. IV vancomycin for 2 weeks is recommended (B-II). Device-related osteoarticular infections Some experts recommend the addition of rifampin 600 mg daily or 300–450 mg twice daily (B-III). 44. For early-onset (,2 months after surgery) or acute 50. Alternatives include the following: linezolid 600 mg PO/IV hematogenous prosthetic joint infections involving a stable twice daily (B-II) or TMP-SMX 5 mg/kg/dose IV every 8–12 h implant with short duration (<3 weeks) of symptoms and (C-III). debridement (but device retention), initiate parenteral therapy 51. For CNS shunt infection, shunt removal is recommen- (refer to antibiotic recommendations for osteomyelitis) plus ded, and it should not be replaced until cerebrospinal ﬂuid rifampin 600 mg daily or 300–450 mg PO twice daily for 2 (CSF) cultures are repeatedly negative (A-II). weeks followed by rifampin plus a ﬂuoroquinolone, TMP- SMX, a tetracycline or clindamycin for 3 or 6 months for hips Brain abscess, subdural empyema, spinal epidural abscess and knees, respectively (A-II). Prompt debridement with device 52. Neurosurgical evaluation for incision and drainage is removal whenever feasible is recommended for unstable recommended (A-II). implants, late-onset infections, or in those with long duration 53. IV vancomycin for 4–6 weeks is recommended (B-II). (.3 weeks) of symptoms (A-II). Some experts recommend the addition of rifampin 600 mg Downloaded from 45. For early-onset spinal implant infections (<30 days after daily or 300–450 mg twice daily (B-III). surgery) or implants in an actively infected site, initial 54. Alternatives include the following: linezolid 600 mg PO/IV parenteral therapy plus rifampin followed by prolonged oral twice daily (B-II) and TMP-SMX 5 mg/kg/dose IV every 8–12 h therapy is recommended (B-II). The optimal duration of (C-III). cid.oxfordjournals.org parenteral and oral therapy is unclear; the latter should be Septic Thrombosis of Cavernous or Dural Venous Sinus continued until spine fusion has occurred (B-II). For late-onset infections (.30 days after implant placement), device removal 55. Surgical evaluation for incision and drainage of contiguous sites of infection or abscess is recommended whenever whenever feasible is recommended (B-II). 46. Long-term oral suppressive antibiotics (eg, TMP-SMX, possible (A-II). The role of anticoagulation is controversial. 56. IV vancomycin for 4–6 weeks is recommended (B-II).

a tetracycline, a ﬂuoroquinolone [which should be given in at GATA Library on January 11, 2011 Some experts recommend the addition of rifampin 600 mg conjunction with rifampin due to the potential emergence of daily or 300–450 mg twice daily (B-III). ﬂuoroquinolone resistance, particularly if adequate surgical 57. Alternatives include the following: linezolid 600 mg PO/IV debridement is not possible should be given in conjunction twice daily (B-II) and TMP-SMX 5 mg/kg/dose IV every 8–12 h with rifampin], or clindamycin) with or without rifampin may (C-III). be considered in selected cases, particularly if device removal not possible (B-III). Pediatric considerations

Pediatric considerations 58. IV vancomycin is recommended (A-II). 47. For children with acute hematogenous MRSA osteomye- VII. What is the role of adjunctive therapies for the treatment of litis and septic arthritis, IV vancomycin is recommended (A-II). If MRSA infections? the patient is stable without ongoing bacteremia or intravascular 59. Protein synthesis inhibitors (eg, clindamycin and line- infection, clindamycin 10–13 mg/kg/dose IV every 6–8 h (to zolid) and intravenous immunoglobulin (IVIG) are not administer 40 mg/kg/day) can be used as empirical therapy if the routinely recommended as adjunctive therapy for the manage- clindamycin resistance rate is low (eg, ,10%) with transition to ment of invasive MRSA disease (A-III). Some experts may oral therapy if the strain is susceptible (A-II). The exact consider these agents in selected scenarios (eg, necrotizing duration of therapy should be individualized, but typically pneumonia or severe sepsis) (C-III). a minimum 3–4-week course is recommended for septic arthritis and a 4–6-week course is recommended for osteomyelitis. VIII. What are the recommendations for vancomycin dosing and 48. Alternatives to vancomycin and clindamycin include the monitoring? following: daptomycin 6 mg/kg/day IV once daily (C-III) or These recommendations are based on a consensus statement of linezolid 600 mg PO/IV twice daily for children >12 years of the American Society of Health-System Pharmacists, the IDSA, age and 10 mg/kg/dose every 8 h for children ,12 years of age and The Society of Infectious Diseases Pharmacists on guidelines (C-III). for vancomycin dosing [3, 4].

Clinical Practice Guidelines d CID 2011:52 (1 February) d 5 Adults i. If the patient has had a clinical and microbiologic response 60. IV vancomycin 15–20 mg/kg/dose (actual body weight) to vancomycin, then it may be continued with close follow-up every 8–12 h, not to exceed 2 g per dose, is recommended in ii. If the patient has not had a clinical or microbiologic patients with normal renal function (B-III). response to vancomycin despite adequate debridement and 61. In seriously ill patients (eg, those with sepsis, meningitis, removal of other foci of infection, an alternative to vancomycin pneumonia, or infective endocarditis) with suspected MRSA is recommended regardless of MIC. infection, a loading dose of 25–30 mg/kg (actual body weight) 70. For isolates with a vancomycin MIC .2 lg/mL (eg, may be considered. (Given the risk of red man syndrome and vancomycin-intermediate S. aureus [VISA] or vancomycin- possible anaphylaxis associated with large doses of vancomycin, resistant S. aureus [VRSA]), an alternative to vancomycin one should consider prolonging the infusion time to 2 h and should be used (A-III). use of an antihistamine prior to administration of the loading X. What is the management of persistent MRSA bacteremia and dose.) (C-III). vancomycin treatment failures in adult patients? 62. Trough vancomycin concentrations are the most 71. A search for and removal of other foci of infection, accurate and practical method to guide vancomycin dosing drainage or surgical debridement is recommended (A-III). (B-II). Serum trough concentrations should be obtained at 72. High-dose daptomycin (10 mg/kg/day), if the isolate is steady state conditions, prior to the fourth or ﬁfth dose.

susceptible, in combination with another agent (e.g. gentamicin Downloaded from Monitoring of peak vancomycin concentrations is not 1 mg/kg IV every 8 h, rifampin 600 mg PO/IV daily or recommended (B-II). 300-450 mg PO/IV twice daily, linezolid 600 mg PO/IV BID, 63. For serious infections, such as bacteremia, infective TMP-SMX 5 mg/kg IV twice daily, or a beta-lactam antibiotic) endocarditis, osteomyelitis, meningitis, pneumonia, and severe should be considered (B-III). SSTI (eg, necrotizing fasciitis) due to MRSA, vancomycin

73. If reduced susceptibility to vancomycin and daptomycin cid.oxfordjournals.org trough concentrations of 15–20 lg/mL are recommended are present, options may include the following: quinupristin- (B-II). 64. For most patients with SSTI who have normal renal dalfopristin 7.5 mg/kg/dose IV every 8 h, TMP-SMX 5 mg/kg/ function and are not obese, traditional doses of 1 g every 12 h dose IV twice daily, linezolid 600 mg PO/IV twice daily, or are adequate, and trough monitoring is not required (B-II). telavancin 10 mg/kg/dose IV once daily (C-III). These options 65. Trough vancomycin monitoring is recommended for may be given as a single agent or in combination with other at GATA Library on January 11, 2011 serious infections and patients who are morbidly obese, have antibiotics. renal dysfunction (including those receiving dialysis), or have XI. What is the management of MRSA infections in neonates? fluctuating volumes of distribution (A-II). Neonatal pustulosis 66. Continuous infusion vancomycin regimens are not 74. For mild cases with localized disease, topical treatment recommended (A-II). with mupirocin may be adequate in full-term neonates and Pediatrics young infants (A-III). 75. For localized disease in a premature or very low- 67. Data are limited to guide vancomycin dosing in birthweight infant or more-extensive disease involving multiple children. IV vancomycin 15 mg/kg/dose every 6 h is sites in full-term infants, IV vancomycin or clindamycin is recommended in children with serious or invasive disease recommended, at least initially, until bacteremia is excluded (B-III). (A-II). 68. The efficacy and safety of targeting trough concentrations of 15–20 lg/mL in children requires additional study but should Neonatal MRSA sepsis be considered in those with serious infections, such as 76. IV vancomycin is recommended, dosing as outlined in bacteremia, infective endocarditis, osteomyelitis, meningitis, the Red Book (A-II) [160]. pneumonia, and severe SSTI (ie, necrotizing fasciitis) (B-III). 77. Clindamycin and linezolid are alternatives for non- IX. How should results of vancomycin susceptibility testing be endovascular infections (B-II). used to guide therapy? The prevalence of MRSA has steadily increased since the first 69. For isolates with a vancomycin minimum inhibitory clinical isolate was described in 1961, with an estimated 94,360 concentration (MIC) <2 lg/mL (eg, susceptible according to cases of invasive MRSA disease in the United States in 2005 [5]. Clinical and Laboratory Standards Institute [CLSI] breakpoints), Initially almost exclusively health care–associated, by the mid- the patient’s clinical response should determine the continued 1990s, MRSA strains were reported as causing infections among use of vancomycin, independent of the MIC (A-III). previously healthy individuals in the community who lacked

6 d CID 2011:52 (1 February) d Liu et al. health care–associated risk factors [6]. Unlike HA-MRSA, these PRACTICE GUIDELINES so-called CA-MRSA isolates are susceptible to many non–ß- lactam antibiotics. Furthermore, they are genetically distinct ‘‘Practice guidelines are systematically developed statements to from HA-MRSA isolates and contain a novel cassette element, assist practitioners and patients in making decisions about ap- SCCmec IV and exotoxin, Panton-Valentine leukocidin (PVL). propriate health care for speciﬁc clinical circumstances’’ [27]. The epidemiology of MRSA has become increasingly complex as Attributes of good guidelines include validity, reliability, re- CA-MRSA and HA-MRSA strains have co-mingled both in the producibility, clinical applicability, clinical ﬂexibility, clarity, community and in health care facilities [7, 8]. Not unexpectedly, multidisciplinary process, review of evidence, and documenta- MRSA disease has had an enormous clinical and economic tion [27]. impact [9, 10]. The wide spectrum of illness caused by MRSA includes SSTIs, METHODOLOGY bacteremia and endocarditis, pneumonia, bone and joint in- Panel Composition fections, CNS disease, and toxic shock and sepsis syndromes. The IDSA Standards and Practice Guidelines Committee CA-MRSA was the most common cause of SSTI in a geo- (SPGC) convened adult and pediatric infectious diseases experts graphically diverse network of emergency departments in the in the management of patients with MRSA. United States [11]; however, there may be differences in local Downloaded from epidemiology to consider when implementing these guidelines. Literature Review and Analysis SSTIs may range in clinical presentation from a simple abscess For the 2010 guidelines, the Expert Panel completed the review or cellulitis to deeper soft-tissue infections, such as pyomyositis, and analysis of data published since 1961. Computerized liter- necrotizing fasciitis, and mediastinitis as a complication of ret- ature searches of PUBMED of the English-language literature ropharyngeal abscess [12–15]. Bacteremia accompanies the were performed from 1961 through 2010 using the terms cid.oxfordjournals.org majority (75%) of cases of invasive MRSA disease [5]. A mul- titude of disease manifestations have been described, including, ‘‘methicillin-resistant Staphylococcus aureus’’ or ‘‘MRSA’’ and but not limited to, infective endocarditis; myocardial, peri- focused on human studies but also included studies from ex- nephric, hepatic, and splenic abscesses; septic thrombophlebitis perimental animal models and in vitro data. A few abstracts with and without pulmonary emboli [16]; necrotizing pneu- from national meetings were included. There were few ran- monia [17–21]; osteomyelitis complicated by subperiosteal ab- at GATA Library on January 11, 2011 domized, clinical trials; many recommendations were developed scesses; venous thrombosis and sustained bacteremia [16, 22, from observational studies or small case series, combined with 23]; severe ocular infections, including endophthalmitis [24]; sepsis with purpura fulminans [25]; and Waterhouse-Frider- the opinion of expert panel members. ichsen syndrome [26]. Process Overview The Expert Panel addressed the following clinical questions in In evaluating the evidence regarding the management of MRSA, the 2010 Guidelines: the Panel followed a process used in the development of other I. What is the management of SSTIs in the CA-MRSA era? IDSA guidelines. The process included a systematic weighting of II. What is the management of recurrent MRSA SSTIs? the quality of the evidence and the grade of recommendation III. What is the management of MRSA bacteremia and (Table 1) [28]. infective endocarditis? IV. What is the management of MRSA pneumonia? Consensus Development Based on Evidence V. What is the management of MRSA bone and joint The Panel met on 7 occasions via teleconference to complete the infections? work of the guideline and at the 2007 Annual Meeting of the VI. What is the management of MRSA infections of the CNS? IDSA and the 2008 Joint Interscience Conference on Antimi- VII. What is the role of adjunctive therapies for the treatment crobial Agents and Chemotherapy/IDSA Meeting. The purpose of MRSA infections? of these meetings was to discuss the questions to be addressed, to VIII. What are the recommendations for vancomycin dosing make writing assignments, and to deliberate on the recom- and monitoring? mendations. All members of the panel participated in the IX. How should results of vancomycin susceptibility testing be preparation and review of the draft guideline. Feedback from used to guide therapy? external peer reviews was obtained. The guideline was reviewed X. What is the management of persistent MRSA bacteremia and endorsed by the Pediatric Infectious Diseases Society, the and vancomycin treatment failures? American College of Emergency Physicians, and American XI. What is the management of MRSA in neonates? Academy of Pediatrics. The guideline was reviewed and

Clinical Practice Guidelines d CID 2011:52 (1 February) d 7 Table 1. Strength of Recommendation and Quality of Evidence

Category/grade Deﬁnition Strength of recommendation A Good evidence to support a recommendation for or against use. B Moderate evidence to support a recommendation for or against use. C Poor evidence to support a recommendation. Quality of evidence I Evidence from >1 properly randomized, controlled trial. II Evidence from >1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferably from .1 center); from multiple time-series; or from dramatic results from uncontrolled experiments. III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

NOTE. Adapted from [28]. Reproduced with the permission of the Minister of Public Works and Government Services Canada. approved by the IDSA SPGC and the IDSA Board of Directors recommended for detection of inducible clindamycin resistance prior to dissemination. in erythromycin-resistant, clindamycin-susceptible isolates and Downloaded from is now readily available [38]. Diarrhea is the most common Guidelines and Conflict of Interest adverse effect and occurs in up to 20% of patients, and Clos- All members of the Expert Panel complied with the IDSA policy tridium difficile–associated disease may occur more frequently, on conflicts of interest, which requires disclosure of any financial compared with other oral agents. [39]. The oral suspension is or other interest that might be construed as constituting an ac- often not well tolerated in children, although this may be cid.oxfordjournals.org tual, potential, or apparent conflict. Members of the Expert Panel overcome with addition of flavoring [40]. It is pregnancy cate- were provided IDSA’s conflict of interest disclosure statement gory B [41]. and were asked to identify ties to companies developing products Daptomycin. Daptomycin is a lipopeptide class antibiotic that might be affected by promulgation of the guideline. In- that disrupts cell membrane function via calcium-dependent formation was requested regarding employment, consultancies, binding, resulting in bactericidal activity in a concentration-de- stock ownership, honoraria, research funding, expert testimony, pendent fashion. It is FDA-approved for adults with S. aureus at GATA Library on January 11, 2011 and membership on company advisory committees. The Panel bacteremia, right-sided infective endocarditis, and cSSTI. It made decisions on a case-by-case basis as to whether an in- should not be used for the treatment of non-hematogenous dividual’s role should be limited as a result of a conflict. Potential MRSA pneumonia, because its activity is inhibited by pulmonary conflicts are listed in the Acknowledgements section. surfactant. It is highly protein bound (91%) and renally excreted. The daptomycin susceptibility breakpoint for S. aureus is <1 lg/ LITERATURE REVIEW mL. Nonsusceptible isolates have emerged during therapy in association with treatment failure[42–45].Althoughthemecha- Antimicrobial therapy nism of resistance is not clear, single-point mutations in mprF,the Clindamycin. Clindamycin is approved by the US Food and lysylphosphatidyglycerol synthetase gene, are often present in such Drug Administration (FDA) for the treatment of serious in- strains [46]. Prior exposure to vancomycin and elevated vanco- fections due to S. aureus. Although not specifically approved for mycin MICs have been associated with increases in daptomycin treatment of MRSA infection, it has become widely used for MICs, suggesting possible cross-resistance [45, 47, 48]. Elevations treatment of SSTI and has been successfully used for treatment in creatinine phosphokinase (CPK), which are rarely treatment of invasive susceptible CA-MRSA infections in children, in- limiting, have occurred in patients receiving 6 mg/kg/day but not cluding osteomyelitis, septic arthritis, pneumonia, and lymph- in those receiving 4 mg/kg/day of daptomycin [49, 50]. Patients adenitis [22, 29–31]. Because it is bacteriostatic, it is not should be observed for development of muscle pain or weakness recommended for endovascular infections, such as infective and have weekly CPK levels determined, with more frequent endocarditis or septic thrombophlebitis. Clindamycin has ex- monitoring in those with renal insufficiency or who are receiving cellent tissue penetration, particularly in bone and abscesses, concomitant statin therapy. Several case reports of daptomycin- although penetration into the CSF is limited [32–34]. In vitro induced eosinophilic pneumonia have been described [51]. The rates of susceptibility to clindamycin are higher among CA- pharmacokinetics, safety, and efficacy of daptomycin in children MRSA than they are among HA-MRSA [35], although there is have not been established and are under investigation [52]. variation by geographic region [29, 36, 37]. The D-zone test is Daptomycin is pregnancy category B.

8 d CID 2011:52 (1 February) d Liu et al. Linezolid Linezolid is a synthetic oxazolidinone and in- Additional study is needed to define the role and optimal dosing hibits initiation of protein synthesis at the 50S ribosome. It is of rifampin in management of MRSA infections. FDA-approved for adults and children for the treatment of Telavancin. Telavancin is a parenteral lipoglycopeptide SSTI and nosocomial pneumonia due to MRSA. It has in vitro that inhibits cell wall synthesis by binding to peptidoglycan activity against VISA and VRSA [53–55]. It has 100% oral chain precursors, causing cell membrane depolarization [75]. It bioavailability; hence, parenteral therapy should only be given if is bactericidal against MRSA, VISA, and VRSA. It is FDA-ap- there are problems with gastrointestinal absorption or if the proved for cSSTI in adults and is pregnancy category C. Cre- patient is unable to take oral medications. Linezolid resistance is atinine levels should be monitored, and dosage should be rare, although an outbreak of linezolid-resistant MRSA infection adjusted on the basis of creatinine clearance, because nephro- has been described [56]. Resistance typically occurs during toxicity was more commonly reported among individuals trea- prolonged use via a mutation in the 23S ribosomal RNA (rRNA) ted with telavancin than among those treated with vancomycin binding site for linezolid [57] or cfr gene-mediated methylation in 2 clinical trials [75]; monitoring of serum levels is not avail- of adenosine at position 2503 in 23SrRNA [58, 59]. Long-term able. use is limited by hematologic toxicity, with thrombocytopenia Tetracyclines. Doxycycline is FDA-approved for the occurring more frequently than anemia and neutropenia, pe- treatment of SSTI due to S. aureus, although not specifically ripheral and optic neuropathy, and lactic acidosis. Although for those caused by MRSA. Although tetracyclines have in myelosuppression is generally reversible, peripheral and optic vitro activity, data on the use of tetracyclines for the treatment Downloaded from neuropathy are not reversible or are only partially reversible of MRSA infections are limited. Tetracyclines appear to be [60]. Linezolid is a weak, nonselective, reversible inhibitor of effective in the treatment of SSTI, but data are lacking to monoamine oxidase and has been associated with serotonin support their use in more-invasive infections [76]. Tetracy- syndrome in patients taking concurrent selective serotonin- cline resistance in CA-MRSA isolates is primarily associated receptor inhibitors [61]. Linezolid causes less bone marrow with tetK [77]. Although the tet(M) gene confers resistance to cid.oxfordjournals.org suppression in children than it causes in adults [62]. The most all agents in the class, tet(K) confers resistance to tetracycline common adverse events in children are diarrhea, vomiting, loose [78] and inducible resistance to doxycycline [79], with no stools, and nausea [63]. The linezolid suspension may not be impact on minocycline susceptibility. Therefore, minocycline tolerated because of taste and may not be available in some may be a potential alternative in such cases. Minocycline is pharmacies. It is considered pregnancy category C. available in oral and parenteral formulations. Tigecycline is Quinupristin-Dalfopristin. Quinupristin-dalfopristin is a glycylcycline, a derivative of the tetracyclines, and is FDA- at GATA Library on January 11, 2011 a combination of 2 streptogramin antibiotics and inhibits protein approved in adults for cSSTIs and intraabdominal infections. synthesis. It is FDA-approved for cSSTI in adults and children .16 It has a large volume of distribution and achieves high years of age. It has been used as salvage therapy for invasive MRSA concentrations in tissues and low concentrations in serum infections in the setting of vancomycin treatment failure in adults (,1 lg/mL) [80]. For this reason, and because it exhibits and children [64–66]. Toxicity, including arthralgias, myalgias, bacteriostatic activity against MRSA, caution should be used nausea, and infusion-related reactions, has limited its use. Qui- in treating patients with bacteremia. The FDA recently issued nupristin-dalfopristin is considered pregnancy category B. a warning to consider alternative agents in patients with se- Rifampin. Rifampin has bactericidal activity against S. au- rious infections because of an increase in all-cause mortality reus and achieves high intracellular levels, in addition to pene- noted across phase III/IV clinical trials. Tetracyclines trating biofilms [67–69]. Because of the rapid development of are pregnancy category D and are not recommended for resistance, it should not be used as monotherapy but may be children ,8 years of age because of the potential for tooth used in combination with another active antibiotic in selected enamel discoloration and decreased bone growth. scenarios. The role of rifampin as adjunctive therapy in MRSA TMP-SMX. TMP-SMX is not FDA-approved for the infections has not been definitively established, and there is treatment of any staphylococcal infections. However, because a lack of adequately powered, controlled clinical studies in the 95%–100% of CA-MRSA strains are susceptible in vitro [81, 82], literature [120]. The potential use of rifampin as adjunctive it has become an important option for the outpatient treatment therapy for MRSA infections is discussed in various sections of SSTI [83–85]. A few studies, primarily involving methicillin- throughout these guidelines. Of note, rifampin dosing is quite susceptible S. aureus (MSSA), have suggested a role in bone and variable throughout the literature, ranging from 600 mg daily in joint infections [86–88]. A few case reports [89] and 1 ran- a single dose or in 2 divided doses to 900 mg daily in 2 or 3 domized trial indicate potential efficacy in treating invasive divided doses [70–74]. The range of rifampin dosing in these staphylococcal infections, such as bacteremia and endocarditis guidelines is suggested on the basis of the limited published data [90]. TMP-SMX is effective for the treatment of purulent SSTI and is considered reasonable on the basis of expert opinion. in children [91]. It has not been evaluated for the treatment of

Clinical Practice Guidelines d CID 2011:52 (1 February) d 9 invasive CA-MRSA infections in children. Caution is advised 4. For outpatients with nonpurulent cellulitis (eg, cellulitis when using TMP-SMX to treat elderly patients, particularly with no purulent drainage or exudate and no associated those receiving concurrent inhibitors of the renin-angiotensin abscess), empirical therapy for infection due to b-hemolytic system and those with chronic renal insufficiency, because of an streptococci is recommended (A-II). The role of CA-MRSA is increased risk of hyperkalemia [92]. TMP-SMX is not recom- unknown. Empirical coverage for CA-MRSA is recommended mended in pregnant women in the third trimester, when it is in patients who do not respond to b-lactam therapy and may be considered pregnancy category C/D, or in infants younger than considered in those with systemic toxicity. Five to 10 days of 2monthsofage. therapy is recommended but should be individualized on the Vancomycin. Vancomycin has been the mainstay of par- basis of the patient’s clinical response. enteral therapy for MRSA infections. However, its efficacy has 5. For empirical coverage of CA-MRSA in outpatients with come into question, with concerns over its slow bactericidal SSTI, oral antibiotic options include the following: clindamycin activity, the emergence of resistant strains, and possible ‘‘MIC (A-II), TMP-SMX (A-II), a tetracycline (doxycycline or creep’’ among susceptible strains [93–95]. Vancomycin kills minocycline) (A-II), and linezolid (A-II). If coverage for both staphylococci more slowly than do b-lactams in vitro, particu- b-hemolytic streptococci and CA-MRSA is desired, options larly at higher inocula (107–109 colony-forming units) [96] and include the following: clindamycin alone (A-II) or TMP-SMX is clearly inferior to b-lactams for MSSA bacteremia and infective or a tetracycline in combination with a b-lactam (eg, endocarditis [97–101]. Tissue penetration is highly variable and amoxicillin) (A-II) or linezolid alone (A-II). Downloaded from depends upon the degree of inflammation. In particular, it has 6. The use of rifampin as a single agent or as adjunctive limited penetration into bone [102], lung epithelial lining fluid therapy for the treatment of SSTI is not recommended (A-III). [103] and CSF [104, 105]. Vancomycin is considered pregnancy 7. For hospitalized patients with complicated SSTI (cSSTI: category C [41]. Vancomycin dosing, monitoring, and suscep- defined as patients with deeper soft-tissue infections, surgical/ tibility testing are discussed in Sections VIII and IX.3 traumatic wound infection, major abscesses, cellulitis, and cid.oxfordjournals.org infected ulcers and burns) SSTI, in addition to surgical debridement and broad-spectrum antibiotics, empirical ther- RECOMMENDATIONS FOR THE MANAGEMENT apy for MRSA should be considered pending culture data. OF PATIENTS WITH INFECTIONS CAUSED BY Options include the following: IV vancomycin (A-I), linezolid MRSA 600 mg PO/IV twice daily (A-I), daptomycin 4 mg/kg/dose IV

once daily (A-I), telavancin 10 mg/kg/dose IV once daily (A-I), at GATA Library on January 11, 2011 I. What is the management of SSTIs in the era of CA-MRSA? clindamycin 600 mg IV/PO three times a day (A-III).A SSTI b-lactam antibiotic (eg, cefazolin) may be considered in hospitalized patients with nonpurulent cellulitis with modifi- 1. For a cutaneous abscess, incision and drainage is the cation to MRSA-active therapy if there is no clinical response primary treatment (A-II). For simple abscesses or boils, (A-II). Seven to 14 days of therapy is recommended but should incision and drainage alone is likely adequate but additional be individualized on the basis of the patient’s clinical response. data are needed to further define the role of antibiotics, if any, 8. Cultures from abscesses and other purulent SSTI are in this setting. recommended in patients treated with antibiotic therapy, 2. Antibiotic therapy is recommended for abscesses associated patients with severe local infection or signs of systemic illness, with the following conditions: severe or extensive disease (eg, patients who have not responded adequately to initial treatment, involving multiple sites of infection) or rapid progression in and if there is concern for a cluster or outbreak (A-III). presence of associated cellulitis, signs and symptoms of systemic illness, associated comorbidities or immunosuppres- Pediatric considerations sion, extremes of age, abscess in area difficult to drain (eg, face, hand, and genitalia), associated septic phlebitis, lack of 9. For children with minor skin infections (such as impetigo) and response to I &D alone (A-III). secondarily infected skin lesions (such as eczema, ulcers, or 3. For outpatients with purulent cellulitis (eg, cellulitis lacerations), mupirocin 2% topical ointment can be used (A-III). associated with purulent drainage or exudate in the absence of 10. Tetracyclines should not be used in children ,8 years of a drainable abscess), empirical therapy for CA-MRSA is age (A-II). recommended pending culture results. Empirical therapy for 11. In hospitalized children with cSSTI, vancomycin is infection due to b-hemolytic streptococci is likely unnecessary recommended (A-II). If the patient is stable without ongoing (A-II). Five to 10 days of therapy is recommended but should bacteremia or intravascular infection, empirical therapy with be individualized on the basis of the patient’s clinical clindamycin 10–13 mg/kg/dose IV every 6–8 h (to administer response. 40 mg/kg/day) is an option if the clindamycin resistance rate is

10 d CID 2011:52 (1 February) d Liu et al. low (eg, ,10%) with transition to oral therapy if the strain is development of resistance, rifampin should not be used as susceptible (A-II). Linezolid 600 mg PO/IV twice daily for monotherapy for the treatment of MRSA infections. The ad- children >12 years of age and 10 mg/kg/dose PO/IV every 8 h junctive use of rifampin with another active drug for the treat- for children ,12 years of age is an alternative (A-II). ment of SSTI is not recommended in the absence of data to support benefit [120]. Evidence Summary The need to include coverage against b-hemolytic strepto- The emergence of CA-MRSA has led to a dramatic increase in cocci in addition to CA-MRSA is controversial and may vary emergency department visits and hospital admissions for SSTIs depending on local epidemiology and the type of SSTI as dis- [106, 107]. For minor skin infections (such as impetigo) and cussed below. Although TMP-SMX, doxycycline, and minocy- secondarily infected skin lesions (such as eczema, ulcers, or cline have good in vitro activity against CA-MRSA, their activity lacerations), mupirocin 2% topical ointment may be effective. against b- hemolytic streptococci is not well-defined [121–123]. For cutaneous abscesses, the main treatment is incision and Clindamycin is active against b- hemolytic streptococci, al- drainage [108]. For small furuncles, moist heat, which helps to though MRSA susceptibility rates may vary by region [85, 124, promote drainage, may be sufficient [109]. It remains contro- 125]. The D-zone test is recommended for erythromycin-re- versial whether antibiotics provide any clinically significant ad- sistant, clindamycin-susceptible isolates to detect inducible ditional benefit, but incision and drainage is likely adequate for clindamycin resistance. The clinical significance of inducible most simple abscesses. Multiple, mostly observational studies clindamycin resistance is unclear because the drug may still be Downloaded from indicate high cure rates (85%–90%) whether or not an active effective for some patients with mild infections; however, its antibiotic is used [11, 81, 110–112]. Two recently published presence should preclude the use of clindamycin for more-se- randomized clinical trials involving adult [113] and pediatric rious infections. [114] patients showed no significant difference in cure rates Outpatients presenting with purulent cellulitis (cellulitis as- when TMP-SMX was compared with placebo; however, there sociated with purulent drainage or exudate in the absence of cid.oxfordjournals.org was a suggestion that antibiotics may prevent the short-term a drainable abscess) should empirically receive oral antibiotics development of new lesions. Two retrospective studies suggest active against CA-MRSA while awaiting culture data. Among improved cure rates if an effective antibiotic is used [85, 115]. patients presenting with purulent SSTI to 11 emergency de- We hope that additional prospective, large-scale studies that are partments throughout the United States, CA-MRSA was the currently already underway will provide more-definitive answers dominant organism, isolated from 59% of patients, followed by

to these questions. Antibiotic therapy is recommended for ab- at GATA Library on January 11, 2011 MSSA (17%); b- hemolytic streptococci accounted for a much scesses associated with the conditions listed in Table 2 [83, 116]. small proportion (2.6%) of these infections [11]. In non- Oral antibiotics that may be used as empirical therapy for CA- purulent cellulitis (cellulitis with no purulent drainage or exu- MRSA include TMP-SMX, doxycycline (or minocycline), clin- date and no associated abscess), ultrasound may be considered damycin, and linezolid. Several observational studies [85, 117] to exclude occult abscess [126, 127]. For nonpurulent cellulitis, and one small randomized trial [84] suggest that TMP-SMX, the absence of culturable material presents an inherent challenge doxycycline, and minocycline are effective for such infections. to our ability to determine its microbiologic etiology and make Clindamycin is effective in children with CA-MRSA SSTI [91, decisions regarding empirical antibiotic therapy. In the pre–CA- 118]. Linezolid is FDA-approved for SSTI but is not superior MRSA era, microbiologic investigations using needle aspiration to less expensive alternatives [119]. Because of the likely or punch biopsy cultures of nonpurulent cellulitis identified b-hemolytic streptococci and S. aureus as the main pathogens. Table 2. In the majority of cases, a bacterial etiology was not identified, but MSSA was the most common pathogen among those who Conditions in which Antimicrobial Therapy is Recommended after Incision and Drainage of an Abscess due to Community-Associated were culture positive [128–133]. A retrospective case-control Methicillin-Resistant Staphylococcus aureus study in children with nonpurulent cellulitis found that, com- Severe or extensive disease (eg, involving multiple sites of pared with b-lactams, clindamycin provided no additional infection) or rapid progression in presence of associated cellulitis benefit, whereas TMP-SMX was associated with a slightly higher Signs and symptoms of systemic illness failure rate [134]. The only prospective study of nonculturable Associated comorbidities or immunosuppression (diabetes cellulitis among hospitalized inpatients found that b-hemolytic mellitus, human immunodeficiency virus infection/AIDS, neoplasm) Extremes of age streptococci (diagnosed by acute- and convalescent-phase se- Abscess in area difficult to drain completely (eg, face, hand, rological testing for anti-streptolysin-O and anti-DNase-B an- and genitalia) tibodies or positive blood culture results) accounted for 73% of Associated septic phlebitis the cases; despite the lack of an identifiable etiology in 27% of Lack of response to incision and drainage alone cases, the overall clinical response rate to b-lactam therapy was

Clinical Practice Guidelines d CID 2011:52 (1 February) d 11 12 Table 3. Recommendations for the Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) d I 015 1February) (1 2011:52 CID Manifestation Treatment Adult dose Pediatric dose Classa Comment Skin and soft-tissue infection (SSTI) Abscess, furuncles, Incision and drainage AII For simple abscesses or boils, carbuncles incision and drainage is likely adequate. Please refer to Table 2 for conditions in which antimicrobial therapy is recommended after d incision and drainage of an i tal. et Liu abscess due to CA-MRSA. Purulent cellulitis Clindamycin 300–450 mg PO TID 10–13 mg/kg/dose PO every AII Clostridium difficile–associated (defined as cellulitis 6–8 h, not to exceed disease may occur more associated with purulent 40 mg/kg/day frequently, compared with drainage or exudate in other oral agents. the absence of a drainable abscess) TMP-SMX 1–2 DS tab PO BID Trimethoprim 4–6 mg/kg/dose, AII TMP-SMX is pregnancy sulfamethoxazole category C/D and not rec 20–30 mg/kg/dose ommended for women in PO every 12 h the third trimester of pregnancy and for children ,2 months of age. Doxycycline 100 mg PO BID <45kg: 2 mg/kg/dose PO AII Tetracyclines are not every 12 h .45kg: recommended for adult dose children under 8 years of age and are pregnancy category D. Minocycline 200 mg 3 1, then 4 mg/kg PO 3 1, then AII 100 mg PO BID 2 mg/kg/dose PO every 12 h Linezolid 600 mg PO BID 10 mg/kg/dose PO every AII More expensive compared 8 h, not to exceed 600 with other alternatives mg/dose Nonpurulent cellulitis b-lactam (eg, cephalexin 500 mg PO QID Please refer to Red Book AII Empirical therapy for (defined as cellulitis with and dicloxacillin) b-hemolytic streptococci is no purulent drainage recommended (AII). Empirical or exudate and no coverage for CA-MRSA is rec- associated abscess) ommended in patients who do not respond to b-lactam therapy and may be considered in those with systemic toxicity. Clindamycin 300–450 mg PO TID 10–13 mg/kg/dose PO every AII Provide coverage for both 6–8 h, not to exceed b-hemolytic streptococci and 40 mg/kg/day CA-MRSA b-lactam (eg, amoxicillin) Amoxicillin: 500 PO mg TID Please refer to Red Book AII Provide coverage for both and/or TMP-SMX or a See above for TMP-SMX See above for TMP- b-hemolytic streptococci tetracycline and tetracycline dosing SMX and tetracycline dosing and CA-MRSA Linezolid 600 mg PO BID 10 mg/kg/dose PO every 8 h, not AII

to exceed 600 mg/dose

Downloaded from from Downloaded cid.oxfordjournals.org at GATA Library on January 11, 2011 11, January on Library GATA at Table 3. (Continued) Manifestation Treatment Adult dose Pediatric dose Classa Comment Provide coverage for both B-hemolytic streptococci and CA-MRSA Complicated SSTI Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h AI/AII 8–12 h Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every AI/AII For children >12 years of age, 8 h, not to exceed 600 mg PO/IV BID. Pregnancy 600 mg/dose category C Daptomycin 4 mg/kg/dose IV QD Ongoing study AI/ND The doses under study in children are 5 mg/kg (ages 12– 17 years), 7 mg/kg (ages 7–11 years), 9 mg/kg (ages 2–6 years) (Clinicaltrials.gov NCT 00711802). Pregnancy category B. Telavancin 10 mg/kg/dose IV QD ND AI/ND Pregnancy category C Clindamycin 600 mg PO/IV TID 10–13 mg/kg/dose PO/IV every AIII/AII Pregnancy category B 6–8 h, not to exceed 40 mg/kg/day Bacteremia and infective endocarditis Bacteremia Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h AII The addition of gentamicin (AII) 8–12 h or rifampin (AI) to vancomycin is not routinely recommended. Daptomycin 6 mg/kg/dose IV QD 6–10 mg/kg/dose IV QD AI/CIII For adult patients, some experts recommend higher dosages of 8–10 mg/kg/dose lnclPatc Guidelines Practice Clinical IV QD (BIII). Pregnancy category B. Infective endocarditis, Same as for bacteremia native valve Infective endocarditis, Vancomycin and 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h BIII prosthetic valve gentamicin and rifampin 8–12 h 1 mg/kg/dose IV every 8 h 1 mg/kg/dose IV every 8 h 300 mg PO/IV every 8 h 5 mg/kg/dose PO/IV every 8 h Persistent bacteremia Please see text d

I 015 1February) (1 2011:52 CID Pneumonia Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h AII 8–12 h Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every 8 h, AII For children >12 years, not to exceed 600 mg/dose 600 mg PO/IV BID. Pregnancy category C. Clindamycin 600 mg PO/IV TID 10–13 mg/kg/dose PO/IV every BIII/AII Pregnancy category B. 6–8 h, not to exceed 40 mg/kg/ day d

Downloaded from from Downloaded cid.oxfordjournals.org at GATA Library on January 11, 2011 11, January on Library GATA at 14 d

I 015 1February) (1 2011:52 CID Table 3. (Continued) Manifestation Treatment Adult dose Pediatric dose Classa Comment

Bone and joint infections Osteomyelitis Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h BII/AII Surgical debridement and 8–12 h drainage of associated soft- tissue abscesses is the mainstay of therapy. (AII). Some experts recommend the addition of rifampin 600 mg d QD or 300–450 mg BID to the i tal. et Liu chosen antibiotic (BIII). For children >12 years of age, linezolid 600 mg PO/IV BID should be used. A single- strength and DS tablet of TMP-SMX contains 80 mg and 160 mg of TMP, respectively. For an 80-kg adult, 2 DS tab- lets achieves a dose of 4 mg/ kg. Daptomycin 6 mg/kg/day IV QD 6–10 mg/kg/day IV QD BII/CIII Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every BII/CIII 8 h, not to exceed 600 mg/dose Clindamycin 600 mg PO/IV TID 10–13 mg/kg/dose PO/IV every BIII/AII 6–8 h, not to exceed 40 mg/kg/day TMP-SMX and rifampin 3.5–4.0 mg/kg/dose PO/IV ND BII/ND every 8–12 h 600 mg PO QD Septic arthritis Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h BII/AII Drainage or debridement of 8–12 h the joint space should always be performed (AII). Daptomycin 6 mg/kg/day IV QD 6–10 mg/kg/dose IV QD BII/CIII Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every BII/CIII 8 h, not to exceed 600 mg/dose Clindamycin 600 mg PO/IV TID 10–13 mg/kg/dose PO/IV every BIII/AII 6–8 h, not to exceed 40 mg/kg/day TMP-SMX 3.5–4.0 mg/kg/dose PO/IV ND BIII/ND every 8–12 h Prosthetic joint, spinal Please see text implant infections Central nervous system

infections

Meningitis Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h BII Some experts recommend the 8–12 h addition of rifampin 600 mg QD or 300–450 mg BID to vancomycin for adult patients (BIII). For children >12 years of age, linezolid 600 mg BID. Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every BII 8 h, not to exceed 600 mg/dose TMP-SMX 5 mg/kg/dose PO/IV every ND CIII/ND 8-12 h Brain abscess, subdural Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h BII Some experts recommend the empyema, spinal 8–12 h addition of rifampin 600 mg epidural abscess QD or 300–450 mg BID to vancomycin for adult patients (BIII). For children >12 years of age, linezolid 600 mg BID. Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every BII 8 h, not to exceed 600 mg/dose

lnclPatc Guidelines Practice Clinical TMP-SMX 5 mg/kg/dose PO/IV ND CIII/ND every 8–12 h Septic thrombosis of Vancomycin 15–20 mg/kg/dose IV every 15 mg/kg/dose IV every 6 h BII Some experts recommend the cavernous or dural 8–12 h addition of rifampin 600 mg venous sinus QD or 300–450 mg BID to vancomycin for adult patients (BIII). For children >12 years of age, linezolid 600 mg BID Linezolid 600 mg PO/IV BID 10 mg/kg/dose PO/IV every BII 8 h, not to exceed 600 mg/dose d

I 015 1February) (1 2011:52 CID TMP-SMX 5 mg/kg/dose PO/IV every ND CIII/ND 8-12 h

NOTE. BID, twice daily; CA-MRSA, community-associated MRSA; DS, double strength; IV, intravenous; ND, no data; PO, oral; QD, every day; TID, 3 times per day; TMP-SMX, trimethoprim-sulfamethoxazole. a Classification of the strength of recommendation and quality of evidence applies to adult and pediatric patients unless otherwise specified. A backslash (/) followed by the recommendation strength and evidence grade will denote any differences in pediatric classification. d

Downloaded from from Downloaded cid.oxfordjournals.org at GATA Library on January 11, 2011 11, January on Library GATA at 96% [135]. Although additional research is needed to charac- iii. Avoid reusing or sharing personal items (eg, disposable terize the microbiology of nonpurulent cellulitis, currently razors, linens, and towels) that have contacted infected skin available data suggests that b-hemolytic streptococci may be the (A-III). primary pathogen. The relative contribution of CA-MRSA, 13. Environmental hygiene measures should be considered in compared with b-hemolytic streptococci and MSSA, remains patients with recurrent SSTI in the household or community unknown, but empirical coverage for CA-MRSA is recom- setting: mended in those who have not responded to b-lactam monotherapy and may be considered in those with systemic toxicity. i. Focus cleaning efforts on high-touch surfaces (ie, surfaces For patients with systemic toxicity and/or rapidly progressive that come into frequent contact with people’s bare skin each or worsening infection despite receipt of appropriate oral anti- day, counters, door knobs, bath tubs, and toilet seats) that may biotics, inpatient management and surgical intervention is rec- contact bare skin or uncovered infections (C-III). ommended. Several antibiotics with MRSA activity are FDA- ii. Commercially available cleaners or detergents appropriate approved for the treatment of adult patients with cSSTI, such as for the surface being cleaned should be used according to label deep soft-tissue infections, surgical and/or traumatic wound instructions for routine cleaning of surfaces (C-III). infections, major abscesses, cellulitis, infected ulcers, and burns: 14. Decolonization may be considered in selected cases if: vancomycin, linezolid, daptomycin, tigecycline, and telavancin

[50, 136–138]. Because of a recent FDA warning indicating an i. A patient develops a recurrent SSTI despite optimizing Downloaded from increased risk in all-cause mortality with tigecycline versus wound care and hygiene measures (C-III). comparator drugs in a pooled analysis of clinical trials, the drug ii. Ongoing transmission is occurring among household members or other close contacts despite optimizing wound was not included in these guidelines, given the availability of care and hygiene measures (C-III). multiple MRSA-active alternatives. Ceftaroline, a novel cepha- losporin antibiotic, may become available in the near future for 15. Decolonization strategies should be offered in conjunction cid.oxfordjournals.org treatment of cSSTI, pending FDA review. When compared with with ongoing reinforcement of hygiene measures and may vancomycin, none of these newer agents have demonstrated include the following: superiority in the primary outcome of clinical cure. There are i. Nasal decolonization with mupirocin twice daily for 5–10 limited published data on the use of clindamycin in adults with days (C-III). cSSTI due to MRSA. Options for the treatment of cSSTI in

ii. Nasal decolonization with mupirocin twice daily for 5– at GATA Library on January 11, 2011 children include clindamycin and linezolid [13, 139]. For hos- 10 days and topical body decolonization regimens with pitalized patients with a nonpurulent cellulitis, a b-lactam an- a skin antiseptic solution (eg, chlorhexidine) for 5–14 days tibiotic (eg, cefazolin) can be considered with modiﬁcation to or dilute bleach baths. (For dilute bleach baths, 1 teaspoon a MRSA-active agent if there is no clinical response [135]. per gallon of water [or ¼ cup per ¼ tub or 13 gallons of The duration of therapy for SSTI has not been well-deﬁned, water] given for 15 min twice weekly for 3monthscanbe although no differences in outcome were observed among adult considered.) (C-III). patients with uncomplicated cellulitis receiving 5 versus 10 days of therapy in a randomized, controlled trial [140]. In the FDA 16. Oral antimicrobial therapy is recommended for the licensing trials for cSSTI, patients were typically treated for 7–14 treatment of active infection only and is not routinely days. Duration of therapy should be individualized on the basis recommended for decolonization (A-III). An oral agent in of the patient’s clinical response. combination with rifampin, if the strain is susceptible, may be considered for decolonization if infections recur despite above measures (CIII). II. What is the management of recurrent MRSA SSTIs? 17. In cases where household or interpersonal transmission is Recurrent SSTIs suspected: 12. Preventive educational messages on personal hygiene and i. Personal and environmental hygiene measures in the appropriate wound care are recommended for all patients with patient and contacts are recommended (A-III). SSTI. Instructions should be provided to: ii. Contacts should be evaluated for evidence of S. aureus i. Keep draining wounds covered with clean, dry bandages infection: (A-III). a. Symptomatic contacts should be evaluated and treated (A- ii. Maintain good personal hygiene with regular bathing and III); nasal and topical body decolonization strategies may be cleaning of hands with soap and water or an alcohol-based considered following treatment of active infection (C-III). hand gel, particularly after touching infected skin or an item b. Nasal and topical body decolonization of asymptomatic that has directly contacted a draining wound (A-III). household contacts may be considered (C-III).

16 d CID 2011:52 (1 February) d Liu et al. 18. The role of cultures in the management of patients with rate of surgical site infections among MSSA nasal carriers [148]. recurrent SSTI is limited: Only 1 small clinical trial examined the role of mupirocin in the management of recurrent MSSA SSTI; a 5-day course of mu- i. Screening cultures prior to decolonization are not pirocin, followed by repeated application on a monthly basis for routinely recommended if at least 1 of the prior infections 1 year, reduced the prevalence of nasal colonization and the was documented as due to MRSA (B-III). number of cases of recurrent SSTI [149]. A trial conducted in the ii. Surveillance cultures following a decolonization regimen era of CA-MRSA found that, although mupirocin decreased the are not routinely recommended in the absence of an active prevalence of nasal colonization, it did not reduce the incidence infection (B-III). of first-time SSTI, compared with placebo [150]. Although it Evidence Summary does not appear to be widespread, a high prevalence of mupir- There are few studies to guide the development of evidence- ocin resistance has been reported among MRSA isolates in some based recommendations on the management of recurrent CA- community settings [151]. Because of the lack of FDA break- MRSA SSTI. Although no standardized definition exists, most points for mupirocin, along with limited availability of com- experts define recurrent disease as 2 or more discrete SSTI ep- mercial tests in the United States, we are unable to provide isodes at different sites over a 6-month period. The pathogenesis specific recommendations on mupirocin susceptibility testing of recurrent infection is unclear and likely involves a complex for individual patients at this time. Clinical laboratories that wish interplay between the pathogen, host colonization, patient be- to perform susceptibility testing may consider validating in- Downloaded from havior, and environmental exposures [141]. The Panel suggests house prepared assays, such as polymerase chain reaction or disk a multifaceted approach that actively engages the patient in diffusion assays [152]. The role of other colonization sites in the personal and environmental hygiene measures applicable to the development of infection or recurrent disease is unknown, and household or community setting [142] while accounting for eliminating nasal colonization alone may be insufficient. Colo- individual preferences. Infected skin and draining wounds nization at nonnasal sites, such as the groin, axilla, and rectum, is cid.oxfordjournals.org should be covered, and sharing of personal items should be more common among those with CA-MRSA than it is among avoided. Commercially available cleaners or detergents should those with CA-MSSA or HA-MRSA [153], although it may be be used for surfaces that come into frequent contact with peo- difficult to distinguish true colonization from transient con- ple’s bare skin each day. tamination at these sites because of active infection. Given the potential role of colonization in the pathogenesis of The potential effectiveness of topical skin antiseptics, such as recurrent SSTI, prevention strategies have also focused on de- chlorhexidine and hexachlorophene, is extrapolated from data at GATA Library on January 11, 2011 colonization, the use of antimicrobial or antiseptic agents to on community outbreaks whereby, when bundled together with suppress or eliminate S. aureus carriage as a means of preventing other interventions, it prevents ongoing transmission and in- auto-infection or transmission. Decolonization measures may fection [154–158]. When used alone, chlorhexidine does not be considered for patients with multiple recurrent SSTI despite appear to be effective; a recent randomized trial found no im- hygiene measures or when there is ongoing transmission in pact of chlorhexidine-impregnated wipes on SSTI rates [159], a well-defined, closely associated cohort [83]. Although de- and at best, it appears to have a transient effect on colonization, colonization strategies are frequently employed, there are no with recolonization occurring soon after discontinuation [161]. published data to support its efficacy in patients with recurrent Hexachlorophene should not be used in infants ,2monthsof MRSA SSTI. The optimal regimen, frequency of application, and age, because it has been linked to adverse neurological outcomes duration of therapy are unclear. Furthermore, it is unknown in newborns. The addition of bleach to bath water has previously whether it will select for or result in replacement with more- been used for treatment of recurrent SSTI in children with ec- resistant or more-virulent strains. zema [162]. In vitro sodium hypochlorite at a concentration Although mupirocin appears to be effective in reducing equivalent to 1/2 cup of bleach in 1/4 tub (13 gallons) of water MRSA colonization, it has not conclusively been shown to pre- kills CA-MRSA after 5 min [163]. Some experts suggest that vent infections among nasal carriers [143, 144], although most bleach baths at a concentration of 1 teaspoon per gallon of bath studies have included patients in the health care setting, where water (1/4 cup per 1/4 tub of water) for 15 min given twice evidence for benefit is limited to certain high-risk populations. A weekly for 3 months is well-tolerated and may be effective. Cochrane Review found that mupirocin was associated with Given the potential for skin irritation if not adequately diluted, a reduction in nosocomial S. aureus (mostly MSSA) infections, clear instructions should be provided. primarily among patients undergoing surgical procedures or No clinical trials have evaluated the role of oral antimicrobials receiving dialysis [145]. No benefit was seen in the 2 studies that for treatment of recurrent CA-MRSA SSTI. A Cochrane review included nonsurgical patients and MRSA carriers [146, 147]. The found no benefit of oral antibiotics for eradication of MRSA combination of mupirocin and chlorhexidine soap reduced the colonization among patients in the health care setting when

Clinical Practice Guidelines d CID 2011:52 (1 February) d 17 compared with placebo, no treatment, or topical antibiotics; 23. A clinical assessment to identify the source and extent of none of these studies examined their impact on infection rates the infection with elimination and/or debridement of other [164]. A systematic review of comparative controlled trials sites of infection should be conducted (A-II). found that a rifampin-based combination, compared with 24. Additional blood cultures 2–4 days after initial positive monotherapy with other oral antibiotics, was more likely to cultures and as needed thereafter are recommended to eradicate S. aureus carriage, but again, no studies examined document clearance of bacteremia (A-II). infection rates as an outcome [165]. Both reviews noted the 25. Echocardiography is recommended for all adult patients emergence of rifampin resistance and adverse events associated with bacteremia. TEE is preferred over TTE (A-II). with systemic agents. 26. Evaluation for valve replacement surgery is recommended While awaiting guidance from ongoing clinical trials, the if large vegetation (.10 mm in diameter), occurrence of >1 Panel suggests mupirocin alone or a combined strategy of mu- embolic event during the ﬁrst 2 weeks of therapy, severe pirocin and topical antiseptics (eg, chlorhexidine and diluted valvular insufﬁciency, valvular perforation or dehiscence, bleach baths) if decolonization is being considered. The optimal decompensated heart failure, perivalvular or myocardial dosage and duration of such regimens is unknown; suggested abscess, new heart block, or persistent fevers or bacteremia dosages are based on several ongoing clinical trials [166–168]. are present (A-II). Oral antimicrobials are not routinely recommended for de- Infective Endocarditis, Prosthetic Valve colonization; they should only be considered in patients who Downloaded from continue to have infections in spite of the other measures. If 27. IV vancomycin plus rifampin 300 mg PO/IV every 8 h for prescribed for decolonization, the optimal regimen and dura- at least 6 weeks plus gentamicin 1 mg/kg/dose IV every 8 h for 2 tion is unknown, although a rifampin-based combination (eg, weeks (B-III). with TMP-SMX or doxycycline) is suggested and administered 28. Early evaluation for valve replacement surgery is in short courses (eg, 5–10 days) to decrease the potential for recommended (A-II). cid.oxfordjournals.org development of resistance. Hygiene measures should be re- Pediatric considerations inforced, and the oral regimen may be offered in conjunction with a topical antiseptic, such as chlorhexidine [169]. Additional 29. In children, vancomycin 15 mg/kg/dose IV every 6 h is studies are needed to guide the prevention of recurrent SSTI. recommended for the treatment of bacteremia and infective endocarditis (A-II). Duration of therapy may range from 2 to 6

III. What is the management of MRSA bacteremia and infective weeks depending on source, presence of endovascular infection, at GATA Library on January 11, 2011 endocarditis? and metastatic foci of infection. Data regarding the safety and Bacteremia and Infective Endocarditis, Native Valve efficacy of alternative agents in children are limited, although daptomycin 6–10 mg/kg/dose IV once daily may be an option 19. For adults with uncomplicated bacteremia (defined as (C-III). Clindamycin or linezolid should not be used if there is patients with positive blood culture results and the following: concern for infective endocarditis or endovascular source of exclusion of endocarditis; no implanted prostheses; follow-up infection but may be considered in children whose bacteremia blood cultures performed on specimens obtained 2–4 days after rapidly clears and is not related to an endovascular focus (B- the initial set that do not grow MRSA; defervescence within 72 h III). of initiating effective therapy; and no evidence of metastatic sites 30. Data are insufficient to support the routine use of of infection), vancomycin (A-II) or daptomycin 6 mg/kg/dose combination therapy with rifampin or gentamicin in children IV once daily (AI) for at least 2 weeks. For complicated with bacteremia or infective endocarditis (C-III); the decision bacteremia (defined as patients with positive blood culture to use combination therapy should be individualized. results who do not meet criteria for uncomplicated bacteremia), 31. Echocardiogram is recommended in children with 4–6 weeks of therapy is recommended, depending on the extent congenital heart disease, bacteremia more than 2–3 days in of infection. Some experts recommend higher dosages of duration, or other clinical findings suggestive of endocarditis daptomycin at 8–10 mg/kg/dose IV once daily (B-III). (A-III). 20. For adults with infective endocarditis, IV vancomycin (A- II) or daptomycin 6 mg/kg/dose IV once daily (A-I) for 6 weeks Evidence Summary is recommended. Some experts recommend higher dosages of MRSA bacteremia and infective endocarditis are serious diseases daptomycin at 8–10 mg/kg/dose IV once daily (B-III). associated with high morbidity, and mortality rates are 30%– 21. Addition of gentamicin to vancomycin is not recommen- 37% for MRSA endocarditis [170, 171]. In addition to antimi- ded for bacteremia or native valve infective endocarditis (A-II). crobial therapy, the source and extent of infection, including 22. Addition of rifampin to vancomycin is not recommended embolic or metastatic foci, should be determined through for bacteremia or native valve infective endocarditis (A-I). careful history and physical examination and imaging, with

18 d CID 2011:52 (1 February) d Liu et al. removal or debridement whenever possible. Vancomycin has were lower than those for patients who received a longer course been the mainstay of therapy for MRSA bacteremia and endo- [186, 187]. For adults, the recommended minimum duration of carditis. However, compared with b-lactam agents, vancomycin therapy for uncomplicated bacteremia is 2 weeks, as defined by: is less effective for the treatment of MSSA bacteremia and en- (1) exclusion of endocarditis, (2) no implanted prostheses (eg, docarditis [98, 99]. Although rifampin or gentamicin is occa- prosthetic valves, cardiac devices, and arthroplasties), (3) follow- sionally used in combination with vancomycin to improve up cultures of blood samples drawn 2–4 days after the initial set outcomes, clinical data do not support this practice. In one that do not grow MRSA, (4) defervescence within 72 h of study, the duration of bacteremia was longer in the rifampin- therapy, and (5) no evidence of metastatic sites of infection [49, combination therapy group than in the vancomycin mono- 188]. If the above criteria are not met, 4–6 weeks of therapy is therapy group [172]. The use of rifampin combination therapy recommended for complicated bacteremia depending on the in a study of native valve S. aureus endocarditis did not improve extent of infection; longer durations of therapy may be needed outcomes but was associated with hepatic adverse effects, drug in those who are slow to clear their bacteremia. Whether the interactions, and the emergence of resistance [173]. Short- entire course must be given parenterally is unknown; there are course, low-dose gentamicin combined with vancomycin for limited data on the use of oral ciprofloxacin in combination MRSA bacteremia and native valve endocarditis was associated with oral rifampin primarily in patients with MSSA right-sided with an increased risk of nephrotoxicity [49, 174]; the duration endocarditis [189, 190]. In the absence of additional studies of bacteremia was comparable to that observed with vancomy- among patients with MRSA, transition from parenteral to oral Downloaded from cin monotherapy [172]. The recommendation to treat pros- therapy should be done cautiously and only in those with un- thetic valve MRSA endocarditis with vancomycin, gentamicin, complicated bacteremia. and rifampin is based on small retrospective studies of methi- TEE is preferred in adults with MRSA bacteremia because of cillin-resistant coagulase-negative staphylococci [175, 176] and its superiority, compared with TTE, for the detection of vege- the 2005 American Heart Association (AHA) Infective Endo- tations [191–193] and identification of complications, such as cid.oxfordjournals.org carditis Guidelines [74]. intracardiac abscess and valvular perforation [194]. In young Daptomycin 6 mg/kg/dose IV once daily is an alternative to children, TTE is likely adequate, given their thin chest wall. vancomycin for adults in the treatment of MRSA bacteremia or Echocardiogram is not routinely recommended for young endocarditis. In a randomized trial, it was noninferior to initial children except in those with congenital heart disease, bacter- low-dose gentamicin plus either vancomycin or an anti- emia of .2–3 days duration, or other clinical findings suggestive staphylococcal penicillin [49]. Emergence of reduced suscepti- of endocarditis [195]. In patients with MRSA bacteremia and at GATA Library on January 11, 2011 bility to daptomycin was observed in several daptomycin-treated infected intravascular or prosthetic devices, a higher relapse and patients who experienced failure of therapy, most of whom had mortality rate has been associated with failure to remove in- deep-seated infections or left-sided endocarditis. Because it ex- fected materials [196, 197]. The management of cardiac device- hibits concentration-dependent killing, some experts recom- related infections was recently reviewed in the 2010 AHA mend doses of up to 8–10 mg/kg, which appear to be safe, guidelines on cardiovascular implantable electronic device in- although additional studies are needed [177, 178]. Whether this fections [198]. Patients with endocarditis should be evaluated higher dosing strategy prevents the emergence of resistance for valve replacement on the basis of clinical and echocardio- [179–181] or improved outcomes is unknown and is under graphic criteria as per AHA guidelines [74, 199]; data suggest investigation. Although daptomycin should not be used in pa- that patients with staphylococcal endocarditis may benefit from tients with pneumonia because of inactivation by pulmonary early surgical intervention [200–204]. surfactant [182], it can be used in septic pulmonary emboli [183]. The safety and efficacy of daptomycin in children have IV. What is the management of MRSA pneumonia? not been established, but it may be effective when given in Pneumonia combination with other agents in children with disseminated 32. For hospitalized patients with severe community-acquired MRSA infections associated with prolonged bacteremia [184]. pneumonia defined by any one of the following: (1) a requirement Doses of 8–10 mg/kg appear to be safe in children, although for ICU admission, (2) necrotizing or cavitary infiltrates, or (3) additional study is needed [185]. Quinopristin-dalfopristin, empyema, empirical therapy for MRSA is recommended pending linezolid, TMP-SMX, and telavancin are not recommended as sputum and/or blood culture results (A-III). first-line therapy for MRSA bacteremia. Their role as salvage 33. For HA-MRSA or CA-MRSA pneumonia, IV vancomycin agents for persistent MRSA bacteremia is discussed in Section X. (A-II) or linezolid 600 mg PO/IV twice daily (A-II) or The duration of therapy for MRSA bacteremia is based on clindamycin 600 mg PO/IV three times daily (B-III) if the several factors. Patients receiving ,14 days of therapy, including strain is susceptible is recommended for 7-21 days, depending those with catheter-associated bacteremia, had success rates that on the extent of infection.

Clinical Practice Guidelines d CID 2011:52 (1 February) d 19 34. In patients with MRSA pneumonia complicated by recommend for or against the use of protein synthesis (eg, toxin) empyema, antimicrobial therapy against MRSA should be used inhibitors, such as clindamycin or linezolid, as adjunctive in conjunction with drainage procedures (A-III). therapy for the treatment of MRSA pneumonia; this topic is discussed further in section VII. Fluoroquinolones may have Pediatric considerations activity against some CA-MRSA isolates, but they are not rou- 35. In children, IV vancomycin is recommended (A-II). If the tinely recommended, because resistance may emerge with patient is stable without ongoing bacteremia or intravascular monotherapy. One small randomized study found that TMP- infection, clindamycin 10–13 mg/kg/dose IV every 6–8 h (to SMX was effective as prophylaxis for MRSA VAP in patients administer 40 mg/kg/day) can be used as empirical therapy if with burns [216], but additional study is needed to determine the clindamycin resistance rate is low (eg, ,10%) with its role in MRSA pneumonia. transition to oral therapy if the strain is susceptible (A-II). Linezolid 600 mg PO/IV twice daily for children >12 years of age and 10 mg/kg/dose every 8 h for children ,12 years of age is V. What is the management of MRSA bone and joint infections? an alternative (A-II). Osteomyelitis

Evidence Summary 36. Surgical debridement and drainage of associated soft- Although it remains an uncommon etiology of community- tissue abscesses is the mainstay of therapy and should be Downloaded from acquired pneumonia (CAP), MRSA has emerged as a cause of performed whenever feasible (A-II). 37. The optimal route of administration of antibiotic therapy severe CAP [17–21], particularly in the context of a preceding or has not been established. Parenteral, oral, or initial parenteral concurrent influenza-like illness, although not exclusively so therapy followed by oral therapy may be used depending on [205]. Empirical therapy for MRSA should be considered in individual patient circumstances (A-III). patients with severe CAP defined by any one of the following: (1) 38. Antibiotics available for parenteral administration include cid.oxfordjournals.org a requirement for ICU admission, (2) necrotizing or cavitary IV vancomycin (B-II) and daptomycin 6 mg/kg/dose IV once infiltrates, or (3) empyema. Empirical coverage for MRSA daily (B-II). Some antibiotic options with parenteral and oral should be discontinued if sputum or blood cultures do not grow routes of administration include the following: TMP-SMX 4 the organism. mg/kg/dose (TMP component) twice daily in combination High failure rates have been observed in the treatment of with rifampin 600 mg once daily (B-II), linezolid 600 mg twice

MRSA pneumonia, particularly ventilator-associated pneumo- at GATA Library on January 11, 2011 daily (B-II), clindamycin 600 mg every 8 h (B-III). nia (VAP) [206–208], which has been attributed to vancomy- 39. Some experts recommend the addition of rifampin cin’s poor penetration into pulmonary tissue and lung epithelial 600 mg daily or 300–450 mg PO twice daily to the anti- lining fluid [209]. The addition of rifampin to vancomycin for biotic chosen above (B-III). For patients with concurrent the treatment of HA-MRSA appears to improve clinical out- bacteremia, rifampin should be added after clearance of comes, compared with treatment with vancomycin alone, in bacteremia. a small, randomized open-label trial, and this deserves addi- 40. The optimal duration of therapy for MRSA osteomyelitis tional study [210]. Linezolid is an alternative to vancomycin for is unknown. A minimum 8-week course is recommended (A- the treatment of MRSA pneumonia, achieving greater levels in II). Some experts suggest an additional 1-3 months (and lung epithelial lining fluid than in plasma [211]. Linezolid and possibly longer for chronic infection or if debridement is not vancomycin were associated with comparable cure rates in 2 performed) of oral rifampin-based combination therapy with prospective studies involving adult patients with nosocomial TMP-SMX, doxycycline/minocycline, clindamycin, or a fluo- pneumonia [212, 213]; a retrospective pooled subgroup analysis roquinolone, chosen on the basis of susceptibilities (C-III). of MRSA cases in these studies found higher cure rates and 41. MRI with gadolinium is the imaging modality of choice, improved survival in the linezolid arm [214]. A randomized particularly for detection of early osteomyelitis and associated study of linezolid versus vancomycin for MRSA VAP found no soft-tissue disease (A-II). ESR and/or CRP level may be helpful significant difference in early microbiologic response rates [215]. to guide response to therapy (B-III). Thus, it is unclear whether 1 drug is definitively superior to the other for treatment of MRSA VAP, and additional studies are Septic Arthritis ongoing. Linezolid has not been compared with vancomycin for 42. Drainage or debridement of the joint space should always the treatment of VAP in children. be performed (A-II). Clindamycin is an alternative to vancomycin for the treat- 43. For septic arthritis, refer to antibiotic choices for ment of MRSA pneumonia in children [29], and there is limited osteomyelitis (#37 above). A 3-4-week course of therapy is data regarding its use in adults [205]. Data are insufficient to suggested (A-III).

20 d CID 2011:52 (1 February) d Liu et al. Device-related osteoarticular infections drainage of adjacent abscesses, along with antimicrobial therapy 44. For early-onset (,2 months after surgery) or acute [217, 218]. Current treatment strategies are based largely on hematogenous prosthetic joint infections involving a stable noncomparative case series, case reports, and animal models and implant with short duration (<3 weeks) of symptoms and are extrapolated from those for MSSA infection. The optimal debridement (but device retention), initiate parenteral therapy route of administration (parenteral vs oral vs initial parenteral (refer to antibiotic recommendations for osteomyelitis) plus therapy followed by oral therapy) has not been clearly estab- rifampin 600 mg daily or 300–450 mg PO twice daily for 2 lished; this decision should be based on individual patient cir- weeks followed by rifampin plus a ﬂuoroquinolone, TMP- cumstances after weighing the pros and cons of each approach. SMX, a tetracycline or clindamycin for 3 or 6 months for hips Compared with oral therapy, parenteral therapy may offer the and knees, respectively (A-II). Prompt debridement with device potential for better compliance, superior serum levels for certain removal whenever feasible is recommended for unstable drugs, and greater historical experience, although at increased implants, late-onset infections, or in those with long duration expense, patient inconvenience, and potential for line-related (.3 weeks) of symptoms (A-II). complications (eg, infections, line malfunction, and thrombo- 45. For early-onset spinal implant infections (<30 days after phlebitis). surgery), or implants in an actively infected site, initial Despite concerns about poor bone penetration and relative parenteral therapy plus rifampin followed by prolonged oral inefﬁcacy in animal models, vancomycin remains the primary therapy is recommended (B-II). The optimal duration of treatment of MRSA osteomyelitis [218–220]. Failure rates of up Downloaded from parenteral and oral therapy is unclear; the latter should be to 35%–46% have been reported [221–223], and compared with continued until spine fusion has occurred (B-II). For late-onset b-lactam therapy, patients with S. aureus osteomyelitis treated infections (.30 days after implant placement), device removal with vancomycin had a 2-fold higher recurrence rate [224]. whenever feasible is recommended (B-II). These unsatisfactory responses to vancomycin have led some

46. Long-term oral suppressive antibiotics (eg, TMP-SMX, experts to recommend the addition of rifampin because of its cid.oxfordjournals.org a tetracycline, a fluoroquinolone [which should be given in excellent penetration into bone and biofilm [219]. In animal conjunction with rifampin due to the potential emergence of models of S. aureus osteomyelitis, therapy with rifampin com- fluoroquinolone resistance, particularly if adequate surgical bined with a second agent is more effective than is therapy with debridement is not possible], or clindamycin) with or without the companion agent given alone [120]. There are no controlled rifampin may be considered in selected cases, particularly if trials of MRSA osteomyelitis, but 2 small trials of MSSA oste- device removal not possible (B-III). omyelitis suggested higher cure rates were associated with re- at GATA Library on January 11, 2011 Pediatric considerations ceipt of rifampin combination therapy [73, 225]. Retrospective studies of rifampin-based regimens for MRSA osteomyelitis 47. For children with acute hematogenous MRSA osteomy- have yielded mixed results, with 1 study indicating cure rates of elitis and septic arthritis, IV vancomycin is recommended (A- up to 80% [226]; however, 1 study showed no added benefit of II). If the patient is stable without ongoing bacteremia or rifampin if debridement occurred [227]. For patients with intravascular infection, clindamycin 10–13 mg/kg/dose IV concurrent bacteremia, rifampin should be added to the treat- every 6–8 h (to administer 40 mg/kg/day) can be used as ment regimen after clearance of bacteremia. Daptomycin is empirical therapy if the clindamycin resistance rate is low (eg, a parenteral alternative to vancomycin. In a noncomparative ,10%) with transition to oral therapy if the strain is study involving adults with osteomyelitis treated with dapto- susceptible (A-II). The exact duration of therapy should be mycin, clinical improvement was noted in 90%, with better individualized, but typically a minimum 3–4-week course is outcomes at 6 mg/kg/day than at lower dosages [228]. Dapto- recommended for septic arthritis and a 4–6-week course is mycin may have benefit when added to standard therapy in recommended for osteomyelitis. children with refractory invasive MRSA disease if osteomyelitis 48. Alternatives to vancomycin and clindamycin include the is present [184]. Susceptibility testing must be performed, be- following: daptomycin 6 mg/kg/day IV once daily (C-III) or cause daptomycin-nonsusceptible isolates have been described linezolid 600 mg PO/IV twice daily for children >12 years of in cases of treatment failure [42, 43, 229–231]. age and 10 mg/kg/dose every 8 h for children ,12 years of age Oral therapies, administered as either primary or step-down (C-III). therapy, appear to be suitable alternatives to prolonged paren- Evidence Summary teral therapy. In a randomized trial involving adult patients with MRSA bone and joint infections arise from hematogenous chronic nonvertebral MSSA osteomyelitis, equivalent cure rates seeding, a contiguous focus of infection, or direct inoculation of 90% were achieved for 8 weeks of oral TMP-SMX (7–8 mg/ from trauma or a medical procedure. Definitive therapy requires kg/day of TMP component) plus rifampin 600 mg once daily surgical debridement of necrotic bone or the joint space and and a 6-week regimen of IV cloxacillin followed by 2 weeks of

Clinical Practice Guidelines d CID 2011:52 (1 February) d 21 oral therapy [86]; there are no data regarding TMP-SMX plus implant infections (<30 days of implant placement), 6 weeks of rifampin involving children with osteomyelitis. In another study parenteral therapy followed by prolonged oral suppressive of MSSA and MRSA osteomyelitis, similar outcomes were ob- therapy until spine fusion resulted in improved outcomes [243]. served in those patients who received prolonged parenteral For late-onset infections (.30 days after implant placement), therapy and those who received oral step-down therapy (.50% implant removal was critical to success. For ankle fractures, 6 of regimens included rifampin in combination with another weeks of therapy after hardware removal appears to be effective agent) following initial parenteral therapy for 2 weeks [221]. [244]. Oral antibiotics that have been used following initial parenteral Drainage and debridement of the intra-articular cavity is es- therapy for the treatment of osteomyelitis include the following: sential for effective treatment of septic arthritis [217]. In chil- clindamycin, linezolid, fluoroquinolones, and doxycycline or dren, surgical debridement of the hips is recommended, whereas minocycline with or without rifampin [221, 222, 226]. Clinda- arthrocentesis may be adequate for other infected joints [245]. mycin achieves good bone concentrations and is highly effective Although a randomized trial in children with septic arthritis for treatment of non–critically ill children with MRSA osteo- demonstrated that 10 days of antibiotics was noninferior to myelitis [34, 232]; there are limited data regarding its use in 30 days of comparable therapy, only 35 episodes of S. aureus adults. Linezolid achieves good concentrations in infected bone; arthritis, none of which involved MRSA, were treated for small case series involving adults and children with MRSA os- 10 days; in 3 of these cases, therapy was extended to 20 days teomyelitis, septic arthritis, or prosthetic joint infections suggest because of inadequate response [246]. Most experts suggest Downloaded from that it is effective [233–237]. Weekly monitoring of complete treating for 3-4 weeks and longer if contiguous osteomyelitis, blood counts is recommended if therapy exceeds 2 weeks; an noted in up to 30% of children, is present [245]. Clinical re- ophthalmologic examination should be performed at 1 month sponse should guide the decision to convert from parenteral to after therapy initiations, because optic neuritis may occur with oral therapy; in one study, switching to oral therapy at 7 days, prolonged treatment [119, 236, 237]. There are limited data compared with switching at 18 days, resulted in similar out- cid.oxfordjournals.org regarding the use of tetracyclines for the treatment of S. aureus comes [247]. osteomyelitis [76, 226], and although fluoroquinolones may be effective, they should only be used in combination with rifampin VI. What is the management of MRSA infections of the CNS? because of the potential for the development of resistance. Meningitis The optimal duration of therapy for osteomyelitis is un- 49. IV vancomycin for 2 weeks is recommended (B-II). Some known. Antibiotic therapy for 8 weeks, compared with shorter at GATA Library on January 11, 2011 experts recommend the addition of rifampin 600 mg daily or durations, have been associated with improved outcomes in 300–450 mg twice daily (B-III). those with S. aureus osteomyelitis [226, 238], whereas undrained 50. Alternatives include the following: linezolid 600 mg PO/IV abscesses and inadequate debridement are associated with re- twice daily (B-II) or TMP-SMX 5 mg/kg/dose IV every 8–12 h lapse rates of 30%–60%, which emphasizes the importance of (C-III). surgical therapy [227, 239]. Some experts suggest oral con- 51. For CNS shunt infection, shunt removal is recommended solidative treatment after a course of parenteral therapy for an and it should not be replaced until CSF cultures are repeatedly additional 1–3 months and possibly longer for treatment of negative (A-II). chronic infection, if debridement is not performed or if in- flammatory markers, such as ESR and CRP level, remain ele- Brain abscess, subdural empyema, spinal epidural abscess vated [222]. In a study of vertebral osteomyelitis, this approach 52. Neurosurgical evaluation for incision and drainage is yielded an 83% cure rate [226]. recommended (A-II). In a randomized study of staphylococcal prosthetic hip and 53. IV vancomycin for 4–6 weeks is recommended (B-II). knee joint infections (which included no infections due to Some experts recommend the addition of rifampin 600 mg MRSA) in patients with early-onset (,2 months after surgery) daily or 300–450 mg twice daily (B-III). infections, stable implants, and , 3weeksofsymptoms,3–6 54. Alternatives include the following: linezolid 600 mg PO/IV months of rifampin-based combination therapy plus surgical twice daily (B-II) and TMP-SMX 5 mg/kg/dose IV every 8–12 h debridement without device removal was found to be effective (C-III). [72]. Rifampin dosing in studies of staphylococcal prosthetic Septic Thrombosis of Cavernous or Dural Venous Sinus joint infections is variable, ranging from 600 mg daily to 300– 450 mg twice daily [72, 240, 241]. Debridement and device re- 55. Surgical evaluation for incision and drainage of moval using a 2-stage exchange arthroplasty is recommended contiguous sites of infection or abscess is recommended for late-onset infections, unstable implants, or a prolonged whenever possible (A-II). The role of anticoagulation is duration (.3 weeks) of symptoms [242]. For early-onset spinal controversial.

22 d CID 2011:52 (1 February) d Liu et al. 56. IV vancomycin for 4–6 weeks is recommended (B-II). vancomycin may be considered in patients not responding to Some experts recommend the addition of rifampin 600 mg standard dosing methods. CSF penetration was increased and daily or 300–450 mg twice daily (B-III). concentrations were almost doubled, compared with standard 57. Alternatives include the following: linezolid 600 mg PO/IV dosing, when vancomycin was administered as a 15 mg/kg twice daily (B-II) and TMP-SMX 5 mg/kg/dose IV every 8–12 h loading dose, followed by continuous infusion of 50–60 mg/kg/ (C-III). day for patients with normal renal function [105]. The regimen was well tolerated, although nephrotoxicity has been associated Pediatric considerations with high doses [263]. Several case reports describe the suc- 58. IV vancomycin is recommended (A-II). cessful use of linezolid [264–267], TMP-SMX [255, 268], and Evidence Summary daptomycin [269] for the treatment of MRSA CNS infections, CNS infections caused by MRSA occur as a complication of but additional research is needed to define their role in the a neurosurgical procedure, in association with a contiguous management of such infections. focus of infection, or hematogenously as a complication of For meningitis in association with a CNS shunt, shunt re- bacteremia or infective endocarditis. Treatment is difficult be- moval with placement of an external ventricular drain is critical cause of the critical location of these infections and the blood to therapy [270–273]. CSF cultures should be repeatedly brain barrier, which limits penetration of systemically admin- negative prior to placement of a new shunt [273]. Retention of istered antibiotics to the site of infection. Thus, surgical drainage infected shunts is associated with a high failure rate despite Downloaded from of focal abscesses and removal of any foreign body, such as an administration of both intraventricular and systemic antibiotics infected shunt, should be performed whenever possible. [274]. Once the shunt has been removed, systemic antimicrobial Resistance to multiple antibiotics and the inability of many therapy is usually effective. Although there are very limited antibiotics to achieve therapeutic concentrations in CSF severely data to guide use, intraventricular vancomycin [248, 275] or limit the choices for antimicrobial therapy of MRSA CNS in- daptomycin [276] may be considered in patients who have cid.oxfordjournals.org fections. CSF penetration of vancomycin is poor, approximately ventricular access or who do not respond to systemic antimi- 1% and 5% for uninflamed and inflamed meninges, respectively, crobial therapy. with maximum CSF concentrations of 2–6 lg/mL [248–250]. Considerable controversy surrounds the use of systemic an- Linezolid has good CSF penetration, as high as 66%, with CSF ticoagulation for septic cavernous or dural sinus thromboses peak and trough concentrations of 7–10 lg/mL and 2.5–6.0 lg/ because of the risk of intracranial hemorrhage [277, 278]. If mL, respectively [251–253]. CSF penetration of TMP-SMX is anticoagulation is used, heparin should be used, because it is at GATA Library on January 11, 2011 similar for uninflamed and inflamed meninges, 13%–53% for reversible, and imaging should be performed to exclude lesions TMP and 17%–63% for SMX; CSF concentrations are 1.9–5.7 predisposing to hemorrhage. lg/mL for TMP and 20–63 lg/mL for SMX after a 10 mg/kg/day dosage and a 50 mg/kg/day dosage, respectively [254, 255]. CSF VII. What is the role of adjunctive therapies for the treatment of penetration of rifampin is 22% and is similar for inflamed and MRSA infections? noninflamed meninges, and bactericidal concentrations are 59. Protein synthesis inhibitors (eg, clindamycin and line- achievable in CSF. A 600-mg dose in adults without inflamed zolid) and IVIG are not routinely recommended as adjunctive meninges produced CSF concentrations of 0.57–1.24 lg/mL therapy for the management of invasive MRSA disease (A-III). [70]. In a rabbit meningitis model, CSF penetration of dapto- Some experts may consider these agents in selected scenarios mycin was 5%–6% with concentrations of 3.2–4.0 lg/mL; values (eg, necrotizing pneumonia or severe sepsis) (C-III). were halved for uninflamed meninges [256, 257]. There are no prospective randomized trials on the treatment Evidence Summary of MRSA infections of the CNS. Vancomycin has been the drug Specific recommendations regarding combination antibiotic of choice, but outcomes have been very poor when it has been therapy for individual disease entities are discussed in the re- used as monotherapy [258, 259]. Because of the limited pene- spective sections of the text. This section will focus on the use of tration of vancomycin across even inflamed meninges, con- protein synthesis inhibitors and IVIG as adjunctive therapy. centrations in CSF (and presumably other CNS sites as well) Data are insufficient to recommend for or against the use of may be marginal when the drug is administered intravenously at protein synthesis inhibitors as adjunctive therapy of invasive standard dosages. Because it achieves bactericidal concentrations disease caused by MRSA. Limited in vitro data suggest that in CSF, some experts recommend rifampin in combination with clindamycin and linezolid inhibit production of staphylococcal vancomycin for meningitis and other CNS infections, despite toxic shock syndrome toxin type 1 and PVL [279–281] and a paucity of clinical data demonstrating benefit of the combi- that linezolid suppresses alpha- and beta-hemolysins, staphylo- nation [120, 260–262]. High-dose, continuous infusion of coccal enterotoxin A and B, and protein A [282]. However,

Clinical Practice Guidelines d CID 2011:52 (1 February) d 23 clindamycin or linezolid in combination with vancomycin can 64. For most patients with SSTI who have normal renal be antagonistic in vitro [283–286], and vancomycin alone was function and are not obese, traditional doses of 1 g every 12 h more effective than vancomycin plus linezolid in a rabbit en- are adequate and trough monitoring is not required (B-II). docarditis model [287]. Existing clinical data are limited to case 65. Trough vancomycin monitoring is recommended for reports for patients with staphylococcal toxic shock syndrome serious infections and patients who are morbidly obese, have [281] and necrotizing/cavitary pneumonia [205, 288], and ad- renal dysfunction (including those receiving dialysis), or have ditional studies are needed. fluctuating volumes of distribution (A-II). The role of IVIG in the management of invasive MRSA dis- 66. Continuous infusion vancomycin regimens are not ease is even less clear. IVIG neutralizes staphylococcal exotoxins, recommended (A-II). including PVL [289], although staphylococcal superantigens Pediatric considerations and exotoxins are less efficiently inhibited by IVIG than by streptococcal superantigens [290]. Children with invasive dis- 67. Data are limited to guide vancomycin dosing in children. ease have higher concentrations of antibody to PVL than do IV vancomycin 15 mg/kg/dose every 6 h is recommended in those with SSTIs [291]; it is unclear whether antibody to PVL in children with serious or invasive disease (B-III). IVIG offers additional benefit. In fact, one study suggests that 68. The efficacy and safety of targeting trough concentrations antibody to PVL may be detrimental [292]. Meta-analyses on of 15–20 lg/mL in children requires additional study but the use of IVIG in sepsis and septic shock have indicated should be considered in those with serious infections, such as Downloaded from a mortality benefit, but no benefit was observed when only high- bacteremia, infective endocarditis, osteomyelitis, meningitis, quality trials were included in the analyses [293–296]. Given the pneumonia, and severe SSTI (ie, necrotizing fasciitis) (B-III). available data, IVIG is not recommended in the management of MRSA disease, although its use may be considered in children Evidence Summary with severe MRSA sepsis [297]. Vancomycin doses of 15–20 mg/kg/day every 8–12 h are rec- cid.oxfordjournals.org ommended for adult patients on the basis of actual body weight VIII. What are the recommendations for vancomycin dosing and and are adjusted for the patient’s estimated creatinine clearance, monitoring? not to exceed 2 g per dose. Weight-based dosing is particularly These recommendations are based on a consensus statement of important in obese patients, who are likely to be underdosed the American Society of Health-System Pharmacists, the IDSA, when conventional dosing strategies of 1 g every 12 h are used. and the Society of Infectious Diseases Pharmacists on guidelines Some experts suggest vancomycin loading doses for serious at GATA Library on January 11, 2011 for vancomycin dosing [3,4]. suspected or documented MRSA infections (sepsis, meningitis, Adults pneumonia, or endocarditis) to enable early achievement of 60. IV vancomycin 15–20 mg/kg/dose (actual body weight) target trough concentrations, although clinical data are lacking every 8–12 h, not to exceed 2 g per dose, is recommended in [298, 299]. A vancomycin loading dose of 25 mg/kg was found patients with normal renal function (B-III). to be safe in a small study [300]. Because of the lack of a clear 61. In seriously ill patients (eg, those with sepsis, meningitis, benefit over intermittent dosing, and because time .MIC is not pneumonia, or infective endocarditis) with suspected MRSA the primary predictor of efficacy [301–303], continuous in- infection, a loading dose of 25–30 mg/kg (actual body weight) fusion vancomycin is not recommended. may be considered. (Given the risk of red man syndrome and The pharmacodynamic parameter that best predicts efficacy possible anaphylaxis associated with large doses of vancomycin, of vancomycin is the ratio of the area under the curve (AUC) to one should consider prolonging the infusion time to 2 h and the MIC (AUC/MIC) [304–306]. A single study involving pa- use of an antihistamine prior to administration of the loading tients with S. aureus lower respiratory tract infections reported dose.) (C-III). that an AUC/MIC >400, compared with an AUC/MIC ,400, 62. Trough vancomycin concentrations are the most accurate was associated with improved clinical response and microbio- and practical method to guide vancomycin dosing (B-II). logic eradication [307]. In a study involving patients with MRSA Serum trough concentrations should be obtained at steady health care–associated pneumonia, mean trough vancomycin state conditions, prior to the fourth or fifth dose. Monitoring levels of 9.4 lg/mL and 20.4 lg/mL correlated with a mean AUC of peak vancomycin concentrations is not recommended (6 standard deviation) of 318 6 111 lgÁh/mL and 418 6 152 (B-II). lgÁh/mL, respectively, although no association between trough 63. For serious infections, such as bacteremia, infective concentrations and clinical response was observed [308]. Ad- endocarditis, osteomyelitis, meningitis, pneumonia, and severe ditional studies are needed to verify the target AUC/MIC >400 SSTI (eg, necrotizing fasciitis) due to MRSA, vancomycin trough but, on the basis of currently available data, vancomycin trough concentrations of 15–20 lg/mL are recommended (B-II). concentrations of 15–20 lg/mL are needed to achieve this target

24 d CID 2011:52 (1 February) d Liu et al. if the MIC of the organism is <1 lg/mL. The probability of i. If the patient has had a clinical and microbiologic response achieving target AUC/MIC of .400 is 100% for vancomycin to vancomycin, then it may be continued with close follow-up MIC of 0.5 lg/mL and 0% for MIC value of 2 lg/mL even if ii. If the patient has not had a clinical or microbiologic aggressive dosing strategies are used [298]. In patients with response to vancomycin despite adequate debridement and normal renal function, up to 3–4 g/day of vancomycin may be removal of other foci of infection, an alternative to vancomycin required to attain target AUC/MIC. is recommended regardless of MIC. Measuring trough serum concentrations, which are predictive 70. For isolates with a vancomycin MIC .2 lg/mL (eg, VISA of AUC/MIC, is the most practical means of monitoring van- or VRSA), an alternative to vancomycin should be used (A-III). comycin. Vancomycin trough concentrations ,10 lg/mL have been associated with treatment failures, perhaps attributable to Evidence Summary variable penetration into tissue compartments and selection of The emergence of hVISA, VISA and VRSA poses an additional vancomycin-heteroresistant S. aureus (hVISA) [309]. Clinical challenge to use of this drug. Although these strains are relatively data to support higher target troughs are limited. A trough >15 uncommon, they are associated with vancomycin treatment lg/mL has not clearly been associated with improved outcomes failures and poor outcomes [235, 309, 320, 321]. As a result, [310] [311], duration of bacteremia, or mortality [308, 312]. MIC breakpoints were lowered by the CLSI in 2006 from <4 lg/ However, to optimize vancomycin pharmacodynamics, improve mL to <2 lg/mL for susceptible strains, with MICs of 4–8 lg/ tissue penetration, and minimize selection of resistant strains, mL and >16 lg/mL now indicating intermediate and resistant Downloaded from the Panel suggests targeting higher trough concentrations strains, respectively. Detection of these strains—in particular, for serious infections due to MRSA. For less serious infections, hVISA, in which a small, resistant subpopulation of cells is including most SSTIs, traditional dosing in the adult present—remains a limitation of susceptibility testing methods patient with normal renal function and weight is likely to be [322–324]. The current ‘‘gold standard’’ for hVISA detection is adequate on the basis of excellent clinical response rates population analysis profile (PAP) divided by the AUC; however, cid.oxfordjournals.org without a more aggressive dosing strategy [50, 136, 138, this method is labor-intensive and impractical for the clinical 313, 314]. Higher vancomycin doses and trough concentrations laboratory [325, 326]. Several less laborious tests, including the may be associated with increased nephrotoxicity [263, 311, macrodilution Etest, Etest glycopeptide resistance detection, and 315, 316] and high-frequency hearing loss in older patients Mueller-Hinton agar with 5 mg/L teicoplanin, are more sensitive [317]. Such investigations are limited by small sample and specific for hVISA detection than are other methods [322, sizes, retrospective design, and co-administration of other 327–329], although the optimal assay most predictive of out- at GATA Library on January 11, 2011 nephrotoxic agents. Clearly, additional prospective studies are comes is unclear. Given current limitations, testing for hVISA is needed, particularly because higher dosing strategies are not routinely recommended. For patients with an isolate with implemented. a vancomycin MIC of 2 lg/mL, particularly those patients with There are limited data to guide vancomycin dosing in children limited or no clinical response to vancomycin therapy, an al- with MRSA. Pharmacodynamic data suggest that higher dosages ternate method, such as Etest, should be performed to improve (60 mg/kg/day) are required to achieve AUC/MIC .400 for detection of VISA [330]. isolates with a vancomycin MIC <1 lg/mL [318], but additional In recent years, several centers have observed an ‘‘MIC creep’’ research is needed. A loading dose of 20–25 mg/kg may be among MRSA isolates characterized as susceptible by CLSI cri- considered in seriously ill children. The efficacy and safety of teria [331, 332], with the principle concern being the gradual loss targeting trough concentrations of 15–20 lg/mL for invasive of vancomycin activity, because clinical failures appear to be infections in children have not been studied but should be more common among those with MIC values of 2 lg/mL than considered in serious infections, such as bacteremia, endo- among those with MIC values ,2 lg/mL [95, 310, 311, 333, 334]. carditis, osteomyelitis, meningitis, pneumonia, and severe SSTI To date, no alternate regimens have been clearly shown to result (ie, necrotizing fasciitis). Vancomycin nephrotoxicity is more in better clinical outcomes in those patients with isolates with common with concomitant aminoglycoside use [319]. vancomycin MICs of 2 lg/mL. In addition, data regarding the presence or absence of ‘‘MIC creep’’ is conflicting and has not been confirmed by other groups [335–338]. In a large multicenter IX. How should results of vancomycin susceptibility testing be study, the frequency of MRSA isolates with an MIC .1 lg/mL as used to guide therapy? determined by reference broth microdilution ranged from 1.6%– 69. For isolates with a vancomycin MIC <2 (eg, susceptible 3.7% and was primarily attributable to clonal dissemination of according to CLSI breakpoints), the patient’s clinical response a USA100 strain with reduced susceptibility to vancomycin [338]. should determine the continued use of vancomycin, indepen- Interpretation of these data is further complicated by limi- dent of the MIC (A-III). tations in currently available susceptibility testing methods and

Clinical Practice Guidelines d CID 2011:52 (1 February) d 25 the considerable variability in MIC results, depending on the vancomycin failures in a randomized trial [49]. Persistent bac- method used. One challenge is that acceptable variability for teremia is associated with worse clinical outcomes [171, 342]. MIC methods is 6 1 doubling dilution [339], which makes it Vancomycin treatment failures have been attributed to the difficult to distinguish between an MIC of 1 versus 2 lg/mL. drug’s slow bactericidal activity, emergence of strains with re- Etest, MicroScan, and BD-Phoenix report MIC values that are duced susceptibility to vancomycin, possible enhanced virulence higher than those reported by reference broth microdilution, of CA-MRSA, and inadequate debridement or retained pros- overcalling susceptible strains as intermediate in some cases, thetic device. Yet, at this time, no alternative agent or regimen whereas the Sensititre and Vitek 2 systems tend to undercall has proven to be superior to vancomycin in achieving clinical resistance [330]. In one study, up to 98% of MICs were reported cure or sterilizing blood cultures, which poses a challenge to the as 1.5 or 2 lg/mL by Etest, but when CLSI broth dilution management of such infections. method was used, only 3% of isolates were found to have The point at which the patient should be considered to have a vancomycin MIC of 2 lg/mL [340]. Because Etest and other experienced treatment failure and alternative therapy sought is methods have a tendency to report MIC results that are higher a complex issue. Because the median time to clearance of MRSA than those reported by reference broth microdilution, it is un- bacteremia is 7–9 days [49, 172], most experts agree that per- known whether the ‘‘MIC creep’’ represents a true phenome- sistent bacteremia at or around day 7 of therapy should prompt non, whether it is a technical artifact that depends on the test an assessment to determine whether a change in therapy is in- method used, or whether it applies to a few institutions as a re- dicated. Several factors should be considered, including the Downloaded from sult of clonal spread. The existence or extent of ‘‘MIC creep’’ for following: (1) the patient’s overall clinical response; (2) vanco- pediatric MRSA isolates is not well characterized. In one mycin trough serum concentrations; (3) results of susceptibility children’s hospital, an increase in the vancomycin MIC for S. testing; and (4) the presence of and ability to remove other foci aureus isolates was observed with Etest but not with broth mi- of infection. The decision to modify therapy and the time frame crodilution testing [341]. Because current susceptibility testing at which this occurs may vary depending on the clinical scenario. cid.oxfordjournals.org methods are unable to reliably distinguish MICs of 1 lg/mL Although modification of therapy should generally be consid- from MICs of 2 lg/mL, the Panel recommends evaluation of the ered if the patient is persistently bacteremic after 1 week of patient’s clinical and microbiologic response along with MIC vancomycin therapy, the threshold to change therapy may be results when making decisions regarding therapy. earlier if the patient’s clinical condition is worsening despite adequate debridement and removal of other foci of infection or X. What is the management of persistent MRSA bacteremia and if the vancomycin MIC is 2 lg/mL, particularly in septic or at GATA Library on January 11, 2011 vancomycin treatment failures in adult patients? critically ill patients. On the other hand, no immediate change in therapy may be indicated if the patient is clinically responding 71. A search for and removal of other foci of infection, and the vancomycin MIC is ,2 lg/mL; in many cases, the drainage or surgical debridement is recommended (A-III). bloodstream will clear with continued vancomycin therapy. 72. High-dose daptomycin (10 mg/kg/ day), if the isolate is In general, when constructing an alternate regimen in the susceptible, in combination with another agent (e.g. gentami- setting of vancomycin treatment failure in adult patients, the cin 1 mg/kg IV every 8 h, rifampin 600 mg PO/IV daily or Panel recommends a change in therapy rather than the addition 300-450 mg PO/IV twice daily, linezolid 600 mg PO/IV BID, of other agents (eg, rifampin and gentamicin) to vancomycin. TMP-SMX 5 mg/kg IV twice daily, or a beta-lactam antibiotic) Among the possible choices, daptomycin has the most rapidly should be considered (B-III). bactericidal activity [343, 344], although the use of daptomycin 73. If reduced susceptibility to vancomycin and daptomycin are to treat patients who have not responded to vancomycin represent, options may include the following: quinupristin- quires special consideration. Isolates with vancomycin MICs >2 dalfopristin 7.5 mg/kg/dose IV every 8 h, TMP-SMX 5 mg/kg/ lg/mL may have daptomycin MICs in the nonsusceptible range dose IV twice daily, linezolid 600 mg PO/IV twice daily, or (.1 lg/mL) and in vitro exposure to vancomycin may select for telavancin 10 mg/kg/dose IV once daily (C-III). These options higher daptomycin MICs [47, 48, 179, 345–347]. Persistent may be given as a single agent or in combination with other bacteremia and clinical failures with daptomycin have been as- antibiotics. sociated with daptomycin MICs .1 lg/mL [49, 348]. The 10- mg/kg dose, which appears to be safe [178], is recommended on Evidence Summary the basis of limited in vitro evidence that suggests that higher Clinical or microbiological failures occur in a substantial pro- doses may suppress the emergence of resistance [179–181] and portion of invasive MRSA infections treated with vancomycin. some clinical data that indicates the potential efficacy of dap- Persistent bacteremia and relapse are common among patients tomycin at 10 mg/kg/day in clearing complicated MRSA bac- with infective endocarditis [171] and account for 17% of the teremia due to strains with a daptomycin MIC of 2 lg/mL [349].

26 d CID 2011:52 (1 February) d Liu et al. Although there are no clinical data, and although additional XI. What is the management of MRSA infections in neonates? study is needed, some experts suggest the use of daptomycin in Neonatal pustulosis combination with another agent, such as gentamicin adminis- 74. For mild cases with localized disease, topical treatment tered at a dosage of 1 mg/kg every 8 h, rifampin, or both drugs if with mupirocin may be adequate in full-term neonates and the strain is susceptible to both [96, 181, 350, 351]. Synergy has young infants (A-III). been described in vitro and in animal models between dapto- 75. For localized disease in a premature or very low- mycin and gentamicin [96, 181, 350–352], daptomycin and ri- birthweight infant or more-extensive disease involving multiple fampin [351, 353], and among all 3 drugs [351], although one sites in full-term infants, IV vancomycin or clindamycin is study suggests that the combination of daptomycin and rifam- recommended, at least initially, until bacteremia is excluded pin may be antagonistic [354]. Once-daily gentamicin at 5 mg/ (A-II). kg may be an alternative to traditional dosing and has a lower risk of nephrotoxicity [355]. Neonatal MRSA sepsis There are even less data to guide the management of patients 76. IV vancomycin is recommended, dosing as outlined in with isolates that are nonsusceptible to both vancomycin and the Red Book (A-II). daptomycin and who are experiencing failure of therapy [324]. 77. Clindamycin and linezolid are alternatives for non- Quinupristin-dalfopristin has been used successfully as salvage endovascular infections (B-II). therapy in patients with vancomycin treatment failure [65], al- Downloaded from though response rates were lower for patients with endocarditis Evidence Summary and bacteremia of unknown source [64]. TMP-SMX is bacte- For neonates with localized pustulosis, clinical experience sug- ricidal in vitro, it but was inferior to vancomycin for the treat- gests that topical mupirocin alone may be effective, although ment of S. aureus infections, although all treatment failures parenteral antibiotic therapy is recommended for more-exten- occurred among those with MSSA infection, whereas all patients sive disease. Lumbar puncture is not necessary in a full-term cid.oxfordjournals.org with MRSA infection were cured [90]. Thymidine release from infant ,30 days of age with localized pustulosis with no signs or damaged host cells and bacteria may limit the efficacy of folate symptoms of sepsis [368]. Vancomycin is the primary treatment antagonists, so caution should be exercised when using TMP- for serious MRSA infections in the neonatal period. There are SMX for the treatment of serious S. aureus infections [356]. limited data on the potential benefit of combination therapy Some experts suggest the addition of gentamicin or rifampin if with rifampin, gentamicin, or daptomycin in neonatal staphy- TMP-SMX is used in salvage therapy. The combination of lococcal sepsis [184, 369]; the decision to use combination at GATA Library on January 11, 2011 daptomycin and trimethoprim-sulfamethoxazole had rapid therapy should be individualized. Experience with clindamycin bactericidal activity compared to daptomycin alone for a dap- and linezolid for serious neonatal MRSA infections is limited, tomycin non-susceptible strain in an in vitro study [371]. but these drugs may be considered for treatment of patients with Linezolid has been used with some success in several series either susceptible isolates who have nonendovascular infections [29, alone or in combination with other agents (eg, rifampin, fusidic 370]. TMP-SMX is not recommended during the immediate acid, gentamicin, amikacin, and carbapenem), but outcomes for neonatal period because of increased risk of kernicterus. patients with left-sided endocarditis have been poor [235, 357– 360]. Of note, rifampin may decrease linezolid levels when given RESEARCH GAPS in combination via an unclear mechanism [361–363]. There is one case report of persistent MRSA bacteremia in a patient with The initial step in developing a rational clinical research agenda tricuspid valve endocarditis that was successfully treated with is the identification of gaps in information. The process of telavancin [364]. The combination of vancomycin plus a b- guideline development, as practiced by the IDSA, serves as lactam has been shown to be synergistic in vitro and in vivo for a natural means by which such gaps are identified. Thus, the VISA and VRSA [365, 366], although additional clinical studies guidelines identify important clinical questions and identify the are needed. More recently, similar observations have been seen quality of evidence supporting those recommendations. Clinical with daptomycin in combination with a b-lactam for treatment questions identified by guideline authors and members of the of infection due to daptomycin nonsusceptible strains [367]. IDSA Research Committee that could inform a MRSA research Hopefully, newer compounds that are under development for agenda are included below. the treatment of MRSA infections will provide more effective alternatives in the future. Bacteremia and Endocarditis Data are insufficient to guide the management of persistent What is the role of echocardiography, and does it improve MRSA bacteremia in children, and the decision regarding use of outcome? Should it be performed routinely in all patients with alternate or combination therapy should be individualized. S. aureus bacteremia or only in certain subsets? Should the

Clinical Practice Guidelines d CID 2011:52 (1 February) d 27 preferred modality be TEE or is a transthoracic examination SSTI sufficient in certain cases? What is the optimal management of nonpurulent cellulitis? How extensive should the work-up be to identify occult foci What is the microbiology of nonpurulent cellulitis (eg, cellulitis of metastatic infection? Is a symptoms-and-signs based ap- with no purulent drainage or exudate and no associated abscess) proach sufficient, or is there a minimal panel of studies that in the era of CA-MRSA? Is initial empirical coverage for MRSA should be performed? necessary? What is the optimal initial therapy? Should vancomycin What is the optimal management of abscesses? Is there any be the first drug of choice for empirical therapy? Should the additional benefit of antibiotics, particularly with regard to patient also receive a b-lactam antibiotic to cover for methicil- impact on recurrent infections and household transmission? lin-susceptible strains pending susceptibility test data? What is optimal management for recurrent SSTIs? What What is the optimal therapy once susceptibility test results is the pathogenesis of recurrent SSTIs? What is the nature of the are available? What is the optimal therapy for patients with interplay between the pathogen, host colonization, and the en- metastatic foci of infection? Is there any role for combination vironment? Is decolonization effective in preventing recurrent therapy? SSTI? If so, what are the appropriate regimens? What specific What regimens should be used in treating persistent or environmental hygiene measures should be taken to prevent relapsing infection? What duration of persisting bacteremia recurrent SSTI and household transmission? signals a need for a change in antibiotic therapy? What alter- Downloaded from native antibiotic regimens should be used? What is the role of PERFORMANCE MEASURES combination therapy? What susceptibility test methods and breakpoint best predict treatment failure, particularly for van- 1. The management of all MRSA infections should include comycin? Should strains with a vancomycin MIC of 2 lg/mL identification, elimination and/or debridement of the primary be considered to be nonsusceptible, and if so, what test should source and other sites of infection when possible (eg, drainage cid.oxfordjournals.org be used to determine MIC? Does infection by so-called hVISA of abscesses, removal of central venous catheters, and de- strains predict treatment failure, and if so, what are the optimal bridement of osteomyelitis). tests for detecting these strains? 2. In patients with MRSA bacteremia, follow-up blood What is the optimal duration of therapy? Is rapid clear- cultures 2–4 days after initial positive cultures and as needed ance of bacteremia an indicator that an abbreviated course of thereafter are recommended to document clearance of antibiotic therapy is sufficient? Are there subsets of patients for bacteremia. at GATA Library on January 11, 2011 whom shorter courses of therapy (ie, less than the generally ac- 3. To optimize serum trough concentrations in adult cepted minimum of 14 days) would be effective? What is the role patients, vancomycin should be dosed according to actual of biological markers (eg, C-reactive protein or procalcitonin) in body weight (15–20 mg/kg/dose every 8–12 h), not to exceed 2 g per dose. Trough monitoring is recommended to achieve determining duration of therapy? What is the optimal duration target concentrations of 15–20 lg/mL in patients with serious of therapy for patients with metastatic foci of infection? MRSA infections and to ensure target concentrations in those who are morbidly obese, have renal dysfunction, or have Osteomyelitis fluctuating volumes of distribution. The efficacy and safety of What is the optimal therapy? What is the importance of targeting higher trough concentrations in children requires bactericidal therapy and antimicrobial bone penetration in the additional study but should be considered in those with severe management of osteomeylitis? What is the efficacy of oral versus sepsis or persistent bacteremia. parenteral therapy? Is oral step-down therapy an alternative to 4. When an alternative to vancomycin is being considered for prolonged parenteral therapy? Is there any benefit of targeting use, in vitro susceptibility should be confirmed and docu- higher vancomycin troughs in osteomyelitis? What are alter- mented in the medical record. natives to vancomycin for the management of osteomyelitis 5. For MSSA infections, a b-lactam antibiotic is the drug of caused by MRSA strains with elevated vancomycin MICs? What choice in the absence of allergy. is the role of rifampin combination therapy? Does early surgical intervention improve outcome? Acknowledgments

What is the optimal management of hardware-associated The Expert Panel wishes to express its gratitude to Drs. Gordon Archer, infections? Frank Lowy, and Brad Spellberg for their thoughtful reviews of earlier drafts What is the optimal duration of therapy? How best should of the guideline. The Expert Panel also recognizes the following for their important contributions in identifying critical gaps where funding of re- laboratory markers of inﬂammation (ESR and CRP level) be search is needed to advance clinical treatment and care: William Burman, used to guide therapy? David M. Margolis, and Louis B. Rice (IDSA Research Committee), Stanley

28 d CID 2011:52 (1 February) d Liu et al. C. Deresinski (IDSA SPGC), and Padma Natarajan (IDSA staff). The 11. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. findings and conclusions of this report are those of the authors and do not aureus infections among patients in the emergency department. N necessarily represent the official position of the Centers for Disease Control Engl J Med 2006; 355:666–74. and Prevention. 12. Lee TC, Carrick MM, Scott BG, et al. Incidence and clinical charac- Financial support. IDSA. teristics of methicillin-resistant Staphylococcus aureus necrotizing Potential conflicts of interest. H.F.C. has received honoraria and re- fasciitis in a large urban hospital. Am J Surg 2007; 194:809–12; search grants and has served as a consultant to Cubist, Ortho-McNeil, discussion, 12–13. Pfizer, Theravance, and Targanta. S. E. C. has received honoraria from 13. Pannaraj PS, Hulten KG, Gonzalez BE, et al. Infective pyomyositis and Forest and RibX, has served as a consultant for Merck and has received myositis in children in the era of community-acquired, methicillin- research support from Astellas, Cubist and AdvanDx. R.D. has received resistant Staphylococcus aureus infection. Clin Infect Dis 2006; 43:953–60. research funding from Pfizer, Clorox, Sanofi Pasteur, Sage, and GeneOhm. 14. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis S.L.K. has received grant funding from Pfizer, has served as MRSA Lead- caused by community-associated methicillin-resistant Staphylococcus ership Advisor to Pfizer, and is participating in a pediatric daptomycin aureus in Los Angeles. N Engl J Med 2005; 352:1445–53. study. A.W.K. has received honoraria and grants from Cubist Pharma- 15. Wright CT, Stocks RM, Armstrong DL, et al. Pediatric mediastinitis as ceuticals, Merck, Wyeth, and Pfizer and has served as a consultant for a complication of methicillin-resistant Staphylococcus aureus retro- Cubist Pharmaceuticals, Theravance, Astellas, Pfizer, Merck, and Ortho- pharyngeal abscess. Arch Otolaryngol Head Neck Surg 2008; McNeil and has owned stock from Cubist Pharmaceutical, Pfizer, and 134:408–13. Johnson and Johnson. D.P.L. has received research support from Cubist, 16. Gonzalez BE, Teruya J, Mahoney DH Jr., et al. Venous thrombosis Johnson & Johnson, and Theravance and has served as a speaker for Cubist. associated with staphylococcal osteomyelitis in children. Pediatrics B.E.M. has served as a consultant and received research support from 2006; 117:1673–9. Johnson & Johnson, Astellas, Pfizer, Cubist, Theravance, Targanta, Sanofi- 17. Francis JS, Doherty MC, Lopatin U, et al. Severe community-onset Aventis, Vicuron Pharmaceuticals, and Wyeth-Ayerst. M.R. has received pneumonia in healthy adults caused by methicillin-resistant Staphy- Downloaded from grants and or has served as a consultant speaker for the Pfizer, Cubist, lococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Theravance/Astellas, Targanta, and Johnson & Johnson. D.A.T. has served Infect Dis 2005; 40:100–7. on the advisory board to Pfizer, Ortho-McNeil, Astellas, Schering-Plough, 18. Hageman JC, Uyeki TM, Francis JS, et al. Severe community-acquired and Replidyne. All other authors: no conflicts. pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis 2006; 12:894–9.

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